CA2339091A1 - Sulphonamide derivatives - Google Patents

Abstract

The present invention relates to the potentiation of glutamate receptor function using certain sulphonamide derivatives. It also relates to novel sulphonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

Description

'.° WO 00/06148 PCT/US99/16962 Sulphonamide Derivatives The present invention relates to the potentiation of glutamate receptor function using ceri~ain sulphonamide derivatives. It also relates to novel sulphonamide derivatives, to processes for their poeparation and to pharmaceutical compositions containing them.
Ln the mammalian central nervous system (CNS), the 1.0 transmission of nerve impulses is cons=rolled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of th_~s receiving neuron.
L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol . Toxi cot . , 21, 16 'i ( 1981 ) ; Monaghan, Bridges, and Cotman, Ann. Rev. Pharmac:ol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans.
Pharm. SC1., 11, 25 {1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), tree development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell- membrane of the neurons are termed "ionotropic". Thi~~ type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of: the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy---' WO 00/06148 PCTIUS99/16962 5-methylisoxazole-4-propionic acid (ANfPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked "metabotropic°' excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol.
Sc~., 14, 13 (1993). Both types of receptors appear not ZO only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends .in Pharmacol. Sci., 11, 508 (1990); Mc~Donald and Johnson, Brain Research Reviews, 15, 41 (1990) .
AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular Pizarmacology 44: 505-510, 1993. It is not yet known how thE~se sub-units are combined in the natural state. Howeve~_°, the structures of certain human variants of each sub-unii~ have been elucidated, and cell lines expressing ~'_ndividual sub-unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulatE: their function.
Thus, European patent application, pubJ.ication number EP-A2-0574257 discloses the human sub-unit variants GluRlB, GluR2B, GluR3A and GluR3B. European patent application, publication number EP-A1-0583917 discloses the human sub-unit variant GluR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid deactivation a.nd desensitization to glutamate. Yamada and Tang, The Journal of Neuroscience, '~ WO 00/06148 PCT/US99/16962 September 1993, 13(9): 3904-3915 and k;athryn M. Partin, J.
Neuroscience, November 1, 1996, 16(21y: 6634-0647. The physiological implications of rapid desensitization, and deactivation if any, are unknown.
It is known that the rapid desensitization and deactivation of AMPA and/or kainic acid receptors to glutamate may be inhibited using certain compounds. This action of these compounds is often referred to in the alternative as "potentiation" of the receptors. One such compound, which selectively potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron. Vol. 11, 1069-1082, 1993. Compounds which potentiate AMPA receptors, like cyclothiazide, are often referred. to as ampakines.
International Patent Application Publication Number WO
9625926 discloses a group of phenylthioalkylsulphonamides, S-oxides and homologs which are said to potentiate membrane currents induced by kainic acid and AMPA.
Ampakines have been shown to improve memory in a variety of animal tests. Staubli et al., Proc. Natl. Acad.
Sci., Vol. 91, pp 777-781, 1994, Neurob.zology, and Arai et al., The Journal of Pharmacology and Experimental Therapeutics, 278: 627-638, 1996.
It has now been found that cyclothiazide and certain sulphonamide derivatives potentiate agonist-induced excitability of human GluR4B receptor expressed in HEK 293 cells. Since cyclothiazide is known to potentiate glutamate receptor function in vivo, it is believed that this finding portends that the sulphonamide derivatives will also potentiate glutamate receptor function in vi vo, and hence that the compounds will exhibit ampakine-like behavior.
In addition, certain sulfonamide derivatives which potentiate glutamate receptor function in a mammal have been disclosed in International Patent Application Publication WO
98/33496 published August 6, 1998.

Accordingly, the present invention provides a compound of the formula:
(~-a)m (~3L°)r X1 ~Lb)~ ~ ,~ C-C-NHS02R2 Rs R~
q I
wherein:
wherein:
La represents (1-4C)alkylene;
Lb represents (1-4C)alkylene;
L° represents (1-4C)alkylene;
r is zero or 1;
m is zero or 1;
n is zero or 1;
q is 1 or 2;
X1 represents 0, S, NRg, C (=0) , OCO, C00, NHC02, 02CNH, CONH, NHCO, SO or 502;
X2 represents O, S, NRl°, C (=O) , OCO, COO, NHC02, 02CNH, CONH, NHCO, SO or 502;
X3 represents O, S, NRll, C (=0) , NHC02, 02CNH, CONH, NHCO, S0 or 502;
R' represents a hydrogen atom, a (1-4C)alkyl group, a (3-8C)cycloalkyl group, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, or a saturated 4 to 7 membered heterocyclic ring containing the group NR1° and a group X as the only hetero ring members, wherein X represents -CH2-, C0, 0, S or NR12 and R12 represents hydrogen or (1-4C);
Rg is hydrogen or (1-4C) alkyl;
Rl° is hydrogen or (1-4C) alkyl, or R1 and R1° together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, 4-_5_ di(1-4C)alkylaminopiperidinyl, morpholino, piperazinyl or N-(1-4C)alkylpiperazinyl group;
R11 is hydrogen or (1-4C)alkyl;
R2 represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoro-alkyl, (1-6C)chloroalkyl, (2-5C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R3R4N in which R3 and R4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and either one of R5, R6, R~ and R8 represents hydrogen; (1-6C) alkyl; aryl (1-6C) alkyl; (2-6C) alkeriyl; aryl (2-6C) alkenyl or aryl, or two of R5, R6, R~ and R8 together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R5, R6, R~
and R8 represent hydrogen; or a pharmaceutically acceptable salt thereof, provided that (1) if m represents zero, then X1 represents C (=0) , CONH, or 502, X2 represents NR1° and R1 and Rlo together with the nitrogen atom to which they are attached form an azetidinyl, piperidinyl, 4-di(1-4C)alkylaminopiperidinyl, piperazinyl or N-(1-4C)alkylpiperazinyl group, and (2) if the group -~2 (La)m (x3l°)r X? _(Lb~n-represents -OCH2CONH-, then R1 does not. represent an optionally substituted aromatic group or an optionally substituted heteroaromatic group:
According to another aspect, the present invention provides a method of potentiating glutamate receptor function in a mammal (including a human) requiring such treatment; which comprises administering an effective amount WO 00/06148 PCTlUS99116.962 of a compound of formula I, or a pharmaceutically acceptable salt thereof as defined herein.
According to another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof as defined herein for the manufacture of a medicament for potentiating glutamate receptor function.
According to yet another aspect, the present invention provides the use of a compound of formula T or a pharmaceutically acceptable salt thereof as defined herein for potentiating glutamate receptor function.
More specifically, it is understood that the following formulas Ia and Ib are included within the scope of formula I:
R~ {x2WtLa)m ~XsL~~ Xt O-b)n / \
H-S-~ Formula la O
1 ~X2~-..~Le)m ~3~~r X5_~~b~n ~ 0 '-'~-~"'~ Formula Ib O
In this specification, the term "potentiating glutamate receptor function" refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitisation or deactivation of AMPA
receptors to glutamate.
A wide variety of conditions may be treated or prevented by the compounds of formula f and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor funcaion. Such conditions include those associated with glutamate hypofunctian, such as psychiatric and neurological ' WO 00/06148 PCTJUS99/16962 disorders, for example cognitive disorders; neuro-degenerative disorders such as Alzheimer's disease; age-related dementias; age-induced memory impairment; movement disorders such as tardive dyskinesia, Hungtington's chorea, myoclonus and Parkinson's disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; and drug-induced psychosis. The compounds of formula I may be further useful for the treatment of sexual dysfunction. The compounds of formula I may also be useful for improving memory (both short term and long term) and learning ability. The present invention provides the use of compounds of formula I for the I5 treatment of each of these conditions.
The term "treating" (or "treat") as used herein includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom.
The present invention includes the pharmaceutically acceptable salts of the compounds defined by formula I. A
compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both i:unctional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base.

WO 00/06I48 PCT/<JS99/16962 _g-Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-b:romophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are ithe sulfate, pyrosuifate, bisulfate, sulfite, bisul:Eite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malanate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-~'.-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as malefic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium _g_ carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.
As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diaster~eomers which have a different configuration at only one ch.iral center are referred to herein as "epimers". The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers.
The term "enantiomeric enrichment"' as used herein refers to the increase in the amount o:E one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which is found using the following equation:
ee = E1 _- E2 X 100 E~ + E~

'" ~ WO 00/06148 PCT/US99116962 wherein E' is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric: enrichment sufficient S to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25°.. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 800. An ee of greater than 90o is preferred, an ee of greater than 95o is most preferred and an ee of greater than 99o is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. Examples of resolutions include recrystallization techniques or chiral chromatography.
Some of the compounds of the presE=_nt invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of t:he present invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific: configuration of a chiral center. The term "R" (rectos) refers to that WO 00/06148 PCT/US99/16.962 configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) 'when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial :list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
As used herein, the term "aromatic group" means the same as "aryl", and includes phenyl and a polycyclic aromatic carbocyclic ring such as naphthyl.
The term "heteroaromatic group" includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered rind containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one to four atoms selecaed from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl and quinolyl.
An optionally substituted aromatic:, an optionally substituted (1-4C)alkylaromatic group, or heteroaromatic group may be unsubstituted or substituted by one or two substituents selected from halogen; nitro; cyano; (1-4C)alkyl; (1-4C)alkoxy; halo(1-4C)alkyl; (1-4C)alkanoyl;

WO 00106148 PCTlUS99/16962 amino; (1-4C)alkylamino; di(1-4C)alkylamino and (2-4C)alkanoylamino.
Examples of particular values for a saturated 4 to 7 membered heterocyclic ring are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, hexahydropyrimidyl, tetrahydro-1,3-oxazinyl, tetrahydro-1,3-thiazinyl and hexahydroazepinyl.
The term (1-6C)alkyl includes (1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
The term (1-4C)alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and the like.
The term (2-6C)alkenyl includes (3-6C)alkenyl.
Particular values are vinyl and prop-2~-enyl.
The term (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy, includes monocyclic and polycyclic groups.
Particular values are cyclopropyl, cyc:lobutyl, cyclopentyl, cyclohexyl and bicyclo[2.2.2)octane. 'rhe term includes (3-6C)cycloalkyl: cyclopropyl, cyclobutyl,, cyclopentyl and cyclohexyl.
The term halogen includes fluorine, chlorine, bromine and iodine.
The terms haloalkyl and halo(I-6C)alkyl, include fluoro(1-6C)alkyl, such as trifluoromei~hyl and 2,2,2-trifluoroethyl, and chloro(1-6C)alkyl such as chloromethyl.
The term (1-4C)alkoxy(I-4C)alkoxy includes methoxymethyl.
The term (1-4C)alkylene includes ethylene, propylene and butylene.
The term thienyl includes thien-2--yl and thien-3-yl.
The term furyl includes fur-2-yl and fur-3-yl.
The term oxazolyl includes oxazol--2-yl, oxazol-4-yl and oxazol-5-yl.

- WO 00/06148 PCT/US99/Ib962 The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl.
The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and [1,2,4]oxadiazol-5-yl.
The term pyrazolyl includes pyraz:ol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
The term thiazolyl includes thia2:ol-2-yl, thiazol-4-yl and thiazol-5-yl.
The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and [1,2,4]thiadiazol-5-yl.
The term_isothiazolyl includes isothiazol-3-yi, isothiazol-4-yl and isothiazol-5-yl.
The term imidazolyl includes imid.azol-2-yl, imidazolyl-4-yl and imidazolyl-5-yl.
The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.
The term tetrazolyl includes tetrazol-5-yl.
The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl and pyridazin-6-yl.
The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl.
The term benzofuryl includes benz~ofur-2-yl and benzofur-3-yl.
The term benzothienyl includes be:nzothien-2-yl and benzothien-3-yl.
The term benzimidazolyl includes benzimidazol-2-yl.
The term benzoxazolyl includes benzoxazol-2-yl.
The term benzothiazolyl includes loenzothiazol-2-yl.
The term indolyl includes indol-2~-yl and indol-3-yl.
The term quinolyl includes quinol~-2-yl.
Examples of particular values for X1 are O and CONH.

' WO 00/06148 PCT/US99/16962 Examples of particular values fox° X2 are O, NHCO, CONH, OCO and OCONH, NR'° wherein R'° represents hydrogen, methyl or, together with R', pyrrolidinyl, piperidinyl, 4-(N,N-dimethylamino)piperidinyl or N-methylpiperazinyl, NHCO, CONH, OCO and OCONH.
An example of a particular value for X3 is O.
Examples of particular values for La are methylene, ethylene, propylene and butylene.
An example of a particular value for Lb is methylene.
An example of a particular value for L° is methylene.
.An example of a particular value for m is 1.
An example of a particular value for n is zero.
Examples of particular values for R1 are hydrogen, methyl, ethyl, propyl, t-butyl, cyclohexyl, phenyl, phenyl substituted with from one to three substituents selected from the group consisting of F, C1, Br, I, (1-4C) alkyls (1-4C)alkoxy, trifluoromethyl, CN, CH3CONH, pyridyl, pyrimidyl, N' -pryridonyl, and, together with X2 when it represents NR'°, pyrrolidinyl, piperidinyl, 4-(N,N-dimethylamino)-piperidinyl or N-methylpiperazinyl.
More particular values of Rr wherein phenyl is substituted with from one to three substituents are as follows:
2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-methoxylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlo:rophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluorometh:ylphenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3, l5-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-dichlorophenyl.

r WO 00!06148 PCT/US99l16962 Examples of values for R2 are mei~hyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, cyclohE~xyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ei.henyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, ar dimethylamino.
Preferably R2 is ethyl, 2-propyl or d~'_methylamino.
Preferably R3 and R4 each represent methyl.
Examples of a (1-6C)alkyl group represented by RS, R6, R~ and R8 are methyl, ethyl and propyl. An example of an aryl (1-C) alkyl group is benzyl. An e~:ample of a (2-6C)alkenyl group is prop-2-enyl. An example of a (3-8C)carbocyclic ring is a cyclopropyl ring.
Preferably R6 and R~ each represents hydrogen.
Preferably R5 and R8 each independently represents hydrogen or (1-4C)alkyl, or together with the carbon atom to which they are attached form a (3-8C) carbocyclic ring.
More preferably R8 represents methyl or ethyl and R5 represents hydrogen or methyl, or RS and R8 together with the carbon atom to which they are attached form a cyclopropyl ring.
Especially preferred are compounds in which R8 represents methyl and R5, R6 and R~ represent hydrogen.
The compounds of formula I may be prepared by (a) reacting a compound of formula Rs Rs R'-X2 (La)m (X3L~)r X? (Lb~~. ~ ~ C_C_NH

R$ R' q with a compound of formula II

in which Z1 represents a leaving atom or group;

(b) for a compound of formula I in which X1 is CONH, reacting a compound of formula R$ Rs NHZ (Lb)~ ~ ~ C-C-~dHS02R2 Rs R~
IV
with a compound of formula R~ X? (La)m {X3L~)r-COZ2 V
in which Z2 represents a hydroxyl group or a leaving atom or group;
(c) for a compound of formula I in which q is 2, coupling a compound of formula R8 Rs Z C-C-NH;iO2R2 ~--/ Rs R7 VI
in which q is 1 and Z3 represents a halogen atom, with a compound of formula R1 X2 tLa)m (XsLc)r X1 (Lb)n ~, ~ Z4 VII
in which q is 1 and Z9 represents a halogen atom;
(d) reacting a compound of formula Rs Rs ZS (La)m {X3L~)~ X (Lb)n ~ ~ C-C-NHS02R2 Rs R7 - q vIII

_17_ in which ZS represents a leaving atom or group, with a compound of formula or (e) reacting a compound of formula R$ i~s H- X~ (L~')n ~ ~ C-(~ -NHS02R2 Rs E~~
x or a protected derivative thereof, with a compound of formula R1 Xz ~La)"' ~x3Lc)r Z~ X I
in which Z6represents a leaving atom o:r group;
followed where necessary and/or desired by forming a pharmaceutically acceptable salt.
In step (a) of the process, the leaving atom or group represented by Z~ may be, for example, a halogen atom such as a chlorine or bromine atom. The reaction is conveniently performed in the presence of a base, far example an alkali metal hydroxide such as sodium hydroxicLe, an alkali metal carbonate such as potassium carbonate, a tertiary amine such as triethylamine or 1,8-diazabi.cyclo[5.4.0]undec-7-ene.
Suitable solvents include halogenated hydrocarbons such as dichloromethane. The reaction is conveniently performed at a temperature in the range of from -20 to 100°C, preferably from -5 to 50°C.
In step (b) of the process, the leaving atom or group represented by Z2 may be, for example, a halogen atom such as a chlorine or bromine atom. It is conveniently generated in situ, for example by reaction of a compound of formula V in which Z2 represents a hydroxyl group wii=h a halogenating agent, such as oxalyl chloride, or with a dehydrating agent, such as a carbodiimide, for example l-~[3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochlc>ride.
The reaction is conveniently performed in the presence of a base, for example an alkali metal. hydroxide such as sodium hydroxide, an alkali metal carbonate such as potassium carbonate, or a tertiary amine such as triethylamine, 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene.
Suitable solvents include halogenated hydrocarbons such as dichloromethane.
The reaction is conveniently performed at a temperature in the range of from -20 to 100°C, preferably from -5 to 50°C.
In step (c) of the process, Z3 and Zq may each represent, for example, a bromine atom. The process is conveniently performed by reacting the compound of formula VII with a strong base, such as an org~anolithium, for example butyl lithium, followed by a t:rialkyl boronic acid, such as trimethylboronic acid. The reactions are conveniently performed in the presence of a solvent, such as an ether, for example tetrahydrofuran. The temperature is conveniently maintained in the range o:E from -78 to 0 °C.
The resultant boronic acid derivative .is then reacted with the compound of formula VI in the presf~nce of a tetrakis (triarylphosphine)palladium(0) catalysis, such as tetrakis (triphenylphosphine)palladium(0), an alcohol, such as n-propyl alcohol and a base such as pota:>sium carbonate.
Convenient solvents for the reaction include ethers such as ethylene glycol dimethyl ether (DME). The temperature at which the reaction is conducted is conveniently in the range of from 0 to 150°C, preferably 75 to 120°C.
In step (d) of the process, the lE~aving atom or group represented by Z5 may be, for example, a halogen atom such as a chlorine atom. Where the compound of formula IX is not basic, the reaction is conveniently performed in the WO 00/06148 PCTIUS99/1.6962 presence of a base, for example a tertiary amine, such as triethylamine or an alkali metal hydride, such as sodium hydride. If desired, the reaction ma;y be performed in the presence of a catalytic amount of an alkali metal iodide, such as potassium iodide. Suitable so:Lvents include aromatic hydrocarbons, such as toluene and amides, such as dimethylformamide. The temperature is conveniently in the range of from 0 to 120°C.
In step (e? of the process, the .Leaving atom or group represented by 26 may be, for example, a halogen atom such as a chlorine atom. The protected derivative may, for example, be protected on nitrogen by a nitrogen protecting group, such as N-t-butoxycarbonyl. Where the compound of formula XI is not basic, the reaction is conveniently performed in the presence of a base, f:or example an alkali metal hydride, such as sodium hydride. If desired, the reaction may be performed in the presence of a catalytic amount of an alkali metal iodide, such as potassium iodide.
Suitable solvents include amides, such as dimethylformamide.
The temperature is conveniently in theo- range of from 0 to 120°C.
For the preparation of compounds of formula I in which X2 represents NHCO, it may be convenient to prepare a corresponding N-protected (e. g. N-t-bu.toxycarbonyl protected) compound of formula I in which R1X2 represents a protected carboxyl group (for example a (1-6C)alkyl ester) by process (e), using as staring material a compound of formula XI in which R1X2 is a protected carboxyl group;
deprotect the protected carboxyl group (for example by hydrolysis using aqueous lithium hydroxide); react this with an amine of formula R1NH2, and then deb>rotect the resultant amide, for example by removing an N-t-butoxycarbonyl protecting group with trifluoroacetic acid.

' WO 00/06148 PCT/US99/16962 The compounds of formula II are ltnown or may be prepared by conventional methods, for example by reducing a corresponding amide or nitrile using borane.
The compounds of formula IV in which n is zero may be prepared by reducing the nitro group in a corresponding nitrophenyl compound, for example by catalytic hydrogenation in the presence of a Group VIII metal catalyst such as palladium on charcoal. The compounds where n is 1 may be prepared by reducing a corresponding nitrile or amide.
The compounds of formula VI may be prepared by reacting a compound of formula R$ Rs Z3 ~ ~ C-C-NH

R$ R' q XII
with a compound of formula Il2 using a method analogous to that of process (a) above.
The compounds of formula X may be prepared by reacting a compound of formula Ra Rs H- X~ (Lb)~ ~ ~ C-C-NH
~ Rs R~ 2 xIII
or a derivative thereof substituted on Xl with a protecting group, for example a benzyl group, with a compound of formula III, according to the method of step (a) above. A
benzyl protecting group may be removed, for example, by reaction with ammonium formate in the presence of palladium on carbon. A t-butoxycarbonyl nitrogen protecting group may be introduced, for example, by reaction of an unprotected compound with di-tert-butyl dicarbonatc>, conveniently in the presence of a base such as 4-dimethylaminopyridine.

WO OOI06148 PCT/tJS99/16962 Suitable solvents include halogenated hydrocarbons, such as dichloromethane.
The compounds of formula XII and XIIT are known or may be prepared by conventional methods, for example by reducing a corresponding amide or nitrite using borane.
The ability of compounds of formula I to potentiate glutamate receptor-mediated response may be determined using fluorescent calcium indicator dyes (Molecular Probes, Eugene, Oregon, Fluo-3) and by measuring glutamate-evoked efflux of calcium into GluR4 transfected HEK293 cells, as described in more detail below.
In one test, 96 well plates containing confluent monolayers of HEK cells stably expressing human GluR4B
(obtained as described in European Patent Application Publication Number EP-A.1-583917) are prepared. The tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 ul of buffer (glucose, lOmM;
sodium chloride, 138mM, magnesium chloride, lmM, potassium chloride, 5mM, calcium chloride, SmM, ~-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], lOmM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutes in the dark with 20 uM Fluo3-AM dye (obtained from Molecular Probes Inc, Eugene, Oregon) in buffer in each well. After the incubation, each well is washed once with 100 ul buffer, 200 ul of buffer is added and the plates a:re incubated for 30 minutes.
Solutions for use in the test are also prepared as follows. 30 ~M, 10 uM, 3 uM and 1 uM dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 uM cyclothiazide solution is prepared by adding 3 ul of 100 mM cyclothiazide to 3 ml of buffer. Control buffer solution is prf~pared by adding i.5 ul DMSO to 498.5 ul of buffer.

Each test is then performed as follows. 200 ul of control buffer in each well is discarded and replaced with 45 pl of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life Sciences International Plc). The buffer is then removed and replaced with 45 ul of buffer and 45 ul of test compound in buffer in appropriates wells. A second fluorescent reading is taken after 5 minutes incubation. 15 pl of 400 u.M glutamate solution is then added to each well (final glutamate concentration 100 uM), and a third reading is taken. The activities of test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 uM cyclothiazide.
In another test, HEK293 cells sta:bly expressing human GluR4 (obtained as described in European Patent Application Publication No. EP-A1-0583917) are used in the electro-physiological characterization of AMPA receptor potentiators. The extracellular recording solution contains (in mM): 140 NaCl, 5 KCl, 10 HEPES, 1 MgCl2, 2 CaCl2, 10 glucose, pH = 7.4 with NaOH, 295 mOsm :kg-1. The intracellular recording solution contains (in mM): 140 CsCl, 1 MgCl2, 10 HEPES, (N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA (ethylen<~-bis(oxyethylene-nitrilo)tetraacetic acid), pH = 7.2 wii:h CsOH, 295 mOsm kg'. With these solutions, recording ;pipettes have a resistance of 2-3 MS2. Using the whole-cell voltage clamp technique (Hamill et a1.(1981)Pfliigers Arch., 391: 85-100), cells are voltage-clamped at -60mV and control current responses to 1 mM glutamate are evoked. Responses to 1 mM
glutamate are then determined in the presence of test WO 00/Ob148 PCT/US99/1.6962 compound. Compounds are deemed active in this test if, at a test concentration of lO uM, they produce a greater than 300 increase in the value of the current evoked by 1 mM
glutamate.
In order to determine the potency of test compounds, the concentration of the test compound, both in the bathing solution and co-applied with glutamate, is increased in half log units until the maximum effect wa:; seen. Data collected in this manner are fit to the Hill equation, yielding an EC50 value, indicative of the potency of the test compound.
Reversibility of test compound activity is determined by assessing control glutamate 1mM responses. Once the control responses to the glutamate challenge are re-established, the potentiation of these responses by 100 uM cyclothiazide is determined by its inclusion in both the bathing solution and the glutamate-containing solution. In this manner, the efficacy of the test compound relative to that of cyclothiazide can be determined.
According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove and a p~h.armaceutically acceptable diluent or carrier.
The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10o by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates; tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrroJ.idone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, tale, magnesium stearate, and mineral oil.
The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent,~or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.

I I

Formulation 1 Hard gelatin capsules are prepared using the following ingredients:
Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
Formulation 2 Tablets each containing 60 mg of active ingredient are made as follows:
Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 24 mesh U.S.
sieve. The granules so produced are oLried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg:
As used herein the term "patient" refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
As used herein the term "effective amount" refers to I5 the amount or dose of the compound whi~~h provides the desired effect in the patient under diagnosis or treatment.
The particular dose of compound administered according to this invention will of course be dei~ermined by the particular circumstances surrounding the case, including the compound administered, the route of adrninistration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compourid may be administered by continuous infusion. A typical daily close will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily dLoses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
The following examples and preparations are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. The reagents and starting materials are readily available to one of ordinary ' ~ WO 00106148 PCT/US99/16962 skill in the art. As used herein, thE: following terms have the indicated meanings: "kg" refers to kilograms; "g" refers to grams; "mg" refers to milligrams; "'fig" refers to micrograms; "mmol" or "mMol" refers to millimoles; "L"
refers to liters; "mL" refers to milliliters; "~,L" refers to microliters; "cm" refers to centimeters; "M" refers to molar; "eq" refers to equivalents; "N" refers to normal;
"ppm" refers to parts per million; "8" refers to parts per million down field .from tetramethylsilane; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury;
"kPa" refers to kilopascals; "psi" refers to pounds per square inch; "bp" refers to boiling point; "mp" refers to melting point; "dec" refers to decomposition; "h" or "hr"
refers to hours; "min" refers to minutes; "sec" refers to seconds; "THF" refers to tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide;
"EDCI HC1" refers to 1-ethyl-3- [3- (dimethylamino)propyl] -carbodiimide hydrochloride; "EtoAc" re:~ers to ethyl acetate;
"EtOH" refers to ethanol; "MeOH" refers to methanol; and "LAH" refers to lithium aluminum hydride.
Preparation 1 2-(4-nitrophenyl)propionitrile A -15°C solution of 4-nitroacetoph.enane (16.5 g, 100 mmol) and tosylmethyl isocyanide (29.3 g, 150 mmol) in methoxyethyl ether (400 mL) was slowly treated with a room temperature solution of the potassium t.-butoxide (28 g, 250 mmol) in t-butanol (200 mL) . The reaction mixture was stirred at -15 °C for 1 h and then allowed to warm to room temperature over night. Water (100 mL) was added to the mixture and the organic layer was extracted with ether (3X200 mL). The combined organic fraction was washed with water (3X200 mL), brine (100 mL), drifsd over sodium sulfate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (Si02, 30%
EtOAc: Hexane) to give 13.6 g (770) of the title compound.
The NMR spectrum was consistent with t:he proposed title structure. Field Desorption Mass Specarum :M+ - 176.
Preparation 2 2-(4-nitrophenyl)propylamine A 0°C solution of the material from Preparation 1 (12.8 g, 67 mmol) in dry THF (200 mL) was treated with borane tetrahydrofuran (1 M in THF, 72 mL, 72 mmo1). The reaction mixture was stirred at room temperature for 16 h. A
solution of THF:MeOH (1:1, 10 mL)and sodium hydroxide (5 N, 40 mL) were added to the reaction mixture stepwise and the mixture was refluxed for 5 h. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was extracted with dichloromethane (3X100 mL). The combined organic fraction was washed with water (3X200 mL), brine (100 mL), dried over potassium carbonate, and concentrated in vacuo to give the crude material which was further purified by flash chromatograpihy (Si02, 5~ MeOH:
CH2C12) to give 8.5 g (71~) of the pure product. The NMR
spectrum was consistent with the proposed title structure.
Field Desorption Mass Spectrum :M+ = 181.
Preparation 3 N-2-(4-nitrophenyl)prop 1 2-propanesulfonamide A 0°C suspension of the material from Preparation 2 (8.2 g, 45.3 mmol) in dichloromethane (200 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-ene (7.6 g, 49.8 mmol) followed by 2-propylsulfonyl chloride i;12 g, 49.8 mmol).

' WO 00/06148 PCT/US99/16962 _29-The reaction mixture was stirred at 0 °C for 1 h and at room temperature for an extra 12 h. The rE:action was stopped by the addition of water (100 mL). The organic layer was extracted with dichloromethane (3X200 mL). The combined organic fraction was washed with water (3X200 mL), brine (100 mL), dried over potassium carbonate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (Si02, 30~ EtOAc: Hexane) to give 8.9 g (680) of the pure product. The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum :M+ - 287.
Preparation 4 N-2-(4-aminophenyl)propyl 2-propanesulfonamide A degassed solution of the material from Preparation 3 (8.75 g, 31 mmol) in ethyl acetate (200 mL) was treated with palladium on carbon (4 g, 50 mot%). The mixture was shaken under 60 psi of hydrogen gas for 2 h. The reaction mixture was filtered through a celite cake and the filtrate was concentrated in vacuo to yield 7.44 g (94%) of the pure product. The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum :M+ - 257.
. Preparation 5 N-2-[4-(chloroacetamido)phe~nyl]propyl 2-propanesulfonamide The product of Preparation 4 (2.0 g, 7.8 mMol) and sodium carbonate (910 mg, 1.1 eq.) were placed into acetone (60 mL) and stirred at ambient temperature under nitrogen. To this mixture, chloroacetyl chloride (971 mg, 1.1 Eq. ) in acetone (10 mL) was added dropwise over a 10 minute period. After 1 hour stirring at ambient temperature, the solution was filtered through celite and concentrated under reduced pressure to yield a white solid (3.0 g). Purification was achieved by silica gel chromatography using the prep. 2000 instrument and eluting with a gradient solvent of mei~hylene chloride to methylene chloride/ethyl acetate 9:1 over a 30 minute period to yield the title compound (2"16 g) as white crystals. m.p. 137.5°-138.5°C. The Nt~IR spectrum was consistent with the proposed structurE:. Ion spray mass spectrum: M+1 = 333.2 Analysis calculated for C14 H21N203C1S: %C, 50.52; $H, 6.36; oN, 8.42. Found: $C, 50.81; oH, 6.42; %N, 8.43.
Preparation 6 4-(N,N-dimethylaminopropyloxy)phenyl bromide 4-bromophenol (5.0 g, 28.9 mmol) and 2-dimethylamino-ethyl chloride hydrochloride (4.6 g, 31.8 mmol) were combined in a mixture of toluene (100 :mL} and 1 M_ NaOH (50 mL) and heated at reflux for 16 h. The layers were separated and the organic phase was washed with 1 M_ NaOH, dried (MgS04) and concentrated to yield 4:2 g of the title compound as a yellow oil which was used without further purification. 1H NMR (400 MHz, CDC13) : 8 2.34 (6H, s) , 2.72 (2H, t), 4.01 (2H, t), 6.73 (2H, m), 7..33 (2H, m).
Preparation 7 2-(4-Bromophenyl)propylamine hydrochloride To a -15 °C solution of 50.0 g (251.2 mmol) of 4-bromo-acetophenone and 49.0 g ( 251.2 mmol} of tosylmethyl iso-cyanide in 800 mL of dry dimethoxyethane was added a hot solution of 50.7 g ( 452.2 mmol) of potassium tert-butoxide in 230 mL of tert-butyl alcohol dropwise at a rate to maintain the temperature below 0 °C . The reaction was stirred at -5 °C far 45 min after addition was camplete.
The cooling bath was removed and the :reaction stirred for 2.5 h more. The mixture was' concentr<~ted in vacuo to a volume of 200 mL and diluted with 500 mL of water. The aqueous mixture was extracted four times with diethyl ether, and the combined organic portions werES dried (MgS04), filtered and concentrated in vacuo. '.the residue was dissolved in 55 mL of tetrahydro-furan and heated to reflux.
30 To the refluxing solution was added s~Lowly dropwise 27.6 mL
( 276.3 mmol) of 10.0 M borane-dimethylsulfide complex.
Refluxing was continued for 20 min after addition was complete. The mixture was cooled to ambient temperature and methanol saturated with hydrogen chloride was added very slowly until pH 2 was achieved. The mixture was concentrated in vacuo and the residue was dissolved in methanol and concentrated in vacuo again. The solid residue was suspended in 125 mL of ethanol, filtered, rinsed with ethanol then diethyl ether. The white: solid was dried in cracuo to afford 25.4 g (400) of the title compound. The filtrate was concentrated in vacuo and suspended in diethyl ether. The solid was filtered, rinsed with diethyl ether and dried in vacuo to afford another 15.6 g (25 °s) of the title compound.
Preparation 8 N-2-(4-Bromophenyl)propyl 2-propylsulfonamide To a suspension of 0.5 g (2.0 mmol) of the product of Preparation 7 in 5 mL of dichloromethane was added 0.6 mL
(4.0 mmol) of triethylamine. The mixture was cooled to 0 °C
and 0.2 mL (2.0 mmol) of isapropylsulfonyl chloride was added. After stirring at 0 °C for 20 min, the mixture was washed once with loo aqueous sodium bisulfate and the WO 00/06148 PCT/US9911b962 organic layer was separated. The aqueous layer was extracted three times with dichloromet;hane. The combined organic portions were dried (Na2S04), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35o ethyl acetate/hexane) afforded 0.2 g (250) of the title compound. Analysis calculated for C12H18N02SBr: ~C, 45.01;
$H, 5.67; %N, 4.37. Found: oC, 45.30; oH, 5.92; oN,4.43.
Field Desorption Mass Spectrum: M+1 = 321 Preparation 9 2-(4-Benzyloxyphenyl)propionitrile To a -15°C solution of 4-benzyloxyacetophenone (500 mg, 2.2 mmol)and tosylmethyl isocyanide (650 mg, 3.3 mmo1) in 10 mL of dry dimethoxyethane was added 2 mL of a warm solution of potassium tert-butoxide (500 mg, 4.5 mmol) in tent-butyl alcohol dropwise at a rate to maintain the temperature below 0°C . The reaction was stirred at -5°C for 45 min after addition was complete. The cooling bath was removed and the reaction stirred for 2.5 h more. The :mixture was concentrated in vacuo to a volume of 2 mL and diluted with 10 mL of water. The organic layer was extracted four times with ethyl acetate, and the combined organic portions were dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Si02, EtOAc/Hexanes; 0-250, gradient) to yield 0.370 g (710) of the title compound. Electrospray Mass Spectrum: 237.1 Analysis calculated for C16H15N0: C; 81.00, H; 6.30, N;

5.90. Found: C; 81.04, H; 6.69, N; 6.17 WO 00106148 PCTIUS99/1b962 Preparation l._0 2--(4-Benzyloxyphenyl)propylamine hydrochloride To an ambient solution of the product of Preparation 9 (1.6 g, 6.75 mmol) in 10 mL of tetrahydrofuran was added borane dimethylsulfide (0.75 mL of they 10 M solution, 7.5 mmol). The reaction mixture was reflu.xed for 1 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuum. The crude product was dissolved in ether and this mixture was treated with a saturated solution of HC1 in methanol (3X20 mL). The resulting white product was precipitated out of ether and collected by filtration to give 1.6 g (8&$) of the title compound. Electospray Mass Spectrum: 242 (M-HCl).
Preparation .L1 N-2-(4-Benzyloxyphenyl)propyl) 2-propanesulfonamide The title compound was prepared from the product of Preparation 10 and 2-propylsulfonyl chloride as described in Preparation 3. Electospray Mass Spectrum: M = 347.2.
Analysis calculated for C1gH25N03S: $C, 65.68; $H, 7.25; $N, 4.03. Found: $C, 65.63; $H, 7.31; $N, 4.07.
Preparation 12 N- t-butoxycarbonyl-N- ( 2- ( 4-hydro:xyphenyl ) propyl ) 2-propanesulfonamide The product of Preparation 11 ( 7.6 g, 23.8 mmol) was dissolved in dichloromethane (100 ml) <~nd to this mixture was added di-tert-butyl dicarbonate (5..71 g, 26.2 mmol) and 4-dimethylaminopyridine ( 1.45 g, 11.9 mmol). The reaction was stirred at ambient temperature for 1 hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine. The organic fraction was dried over magnesium sulfate and concentrated under vacuo.
The protected sulfonamide (9.00 g, 21.0 mmol) was dissolved in ethyl acetate: H20 (5:1) and ammonium formatP l ~.n n 31.5 mmol) added to the mixture. Then palladium an carbon (100) (0.9 g) was added to the reaction and this was stirred at ambient temperature for ~ hours. The suspension was filtered through celite and the resulting solution concentrated in vacuo to give 5.51 g (78%) of the title product.
Electrospray Mass Spectrum: M = 356..2.
Analysis calculated for C15H23N~5S: %C, 57.12; oH, 7.61; oN, 3.92. Found: oC, 57.41; oH, 7.66; oN, 3.83.
Preparation 13 N-2-[4-(2-chloroethyl)oxyph~~nyl]propyl 2-propanesulfonamide The product of Preparation 12 (4 <~, 11.2 mmol) was dissolved in acetone and potassium carbonate (4.64 g, 33.6 mmol) was added. After 30 minutes 1-bromo-2-chloroethane (1.12 mL, 13.44 mmol) was added to the reaction and the mixture was heated under reflux while stirring for 24 hours.
The reaction mixture was partitioned bEaween ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo.
Chromatography ( Si02, 10o ethyl acetate/hexane) gave 1.5 g (320) of the pure product. Electrospray Mass Spectrum:
419.2. Analysis calculated for ClgH3oC1NO5S.H20: ~C, 53.20; gH, 7.28; oN, 3.26. Found: oC, 53.10; oH, 6.27;
oN, 3.59.

° ' WO 00/06148 PCT/US99/16962 Preparation 14 N-tertbutoxyacetyl-2-(4-(2-chloroethoxy)-phenyl) propyl-2-pro anesulfonamide.
To a stirred mixture of N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide (4.0 g, 11.2 mmol) in acetone (40 mL) was added potassium carbonate (4.64 g, 33.6 mmol) under nitrogen. The resulting mixture was stirred 30 minutes at ambient temperature. Next, 1-bromo-2-chloroethane (1.12 ml, 13.4 mmol ) was added and the resulting mixture was heated to reflux while stirring for 48 h. The resulting mixture was cooled and partitioned between ethyl acetate and water. The organic :Layer was washed with water (2X50 mL) and brine (1X50 mL} , dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.5 g (32%) of the pure title compound.
Field Desorption Mass Spectrum: M = 419.2 Analysis for C19H3oC1NO5S
Theory: C, 54.34; H, 7.20; N, 3.34.
Found: C, 54.24; H, 7.36; N, 3.33.
Preparation 15 N-(4-fluorobenzyl)-chloroacetamide.
To a stirred mixture of 4-fluorobenzylamine (685 uL, 6.0 mmol) and dry tetrahydrofuran (20mL) was added triethylamine (1.25 mL, 9.Ommol) under nitrogen. The resulting mixture was stirred for 10 minutes at ambient temperature. Next, chloroacetyl chloride (477 uL, 6.Ommo1) was added and the resulting mixture was stirred for 1 h. at ambient temperature. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2X20 mL) and brine (1X20 mL), dried over magnesium sulfate, and filtered. Evaporation of the ' ' WO 00/06148 PCTltJS99/16962 filtrate ~.n vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.09 g (91~) of the pure title compound.
Mass Spectrum: MS -1 - 200.1 Analysis for C9H9C1FN0 Theory: C, 53.61; H, 4.50; N, 6.95.
Found: C, 53.39; H, 4.52; N, 7.01:
Preparation 16 N- t-butoxycarbonyl-N- ( 2- ( 4 (methoxyacetyl)oxy)phenyl)propyl} 2--propanesulfonamide.
A solution of phenol from Preparation 12 (l0 g, 28 mmol) in dry dimethylformamide (70 ml) was treated gradually with sodium hydride (1.35 g, 33.6 mmol;l. The mixture was stirred for 1 hour at room temperature and then was treated with methyl bromoacetate (5.14 g, 33.6 mmol). The reaction mixture was stirred at 60 °C for 6 hour's. The resulting mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water (2x100 ml}
and brine (1x100 ml), dried over sodiunn sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane (10 o to 30~) gave 7 g (580) of the title compound.
Electrospray Mass Spectrum: 429 Analysis for C2oH31NO~S.HBr:
Theory: C, 53.41; H, 7.00; N, 3.11.
Found C, 53.25; H, 6.66; N, 3.71.

Preparation 17 N-t-butoxycarbonyl-N-(2-(4-(hydroxyacetyl}
oxy)phenyl)propyl) 2-propanesulfonamide.
A solution of phenol from Preparation 16 (6.7 g, 15.6 mmol) in THF:MeOH:H20 (78 ml of 3:2:1) was treated with lithium hydroxide (0.94 g, 23.4 mmo1). The mixture was stirred for 12 hour at room temperature. The resulting mixture was partitioned between ethyl acetate and aqueous HCl (100). The organic layer was washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo gave 5.7 g (880) of the title compound.
Preparation 18 Pip-Pip HOBT.
A solution of 4-chloro-3-nitrobenzyl sulfonylchloride (7.68 g, 30 mmol) in dry dichlorometane (120 mL) was added dropwise to a solution of triethylami.ne (5 mL, 36 mmol) and 4-piperidinopiperidine (5.04 g, 30 mmo.l) in dichloromethane (30 ml). The mixture was stirred for 3 hour at room temperature. The resulting mixture was partitioned between dichloromethane and aqueous sodium hyd.rogensulfate (10~).
The organic layer was washed with sodium hydrogensulfate solution (2X100 mL) and brine (1x100 mL), dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo gave quantitative yield of the orange solid which was added to a 95:5 mixture of EtOH:MeOH (200 mL}. This mixture was treated with hydrazine hydrate (60 mL).
The resulting mixture was refluxed for 3 hours. The unreacted hydrazine and water were removed under reduced pressure. EtOH (50 mL) was added to t:he resulting product and the solvent was removed in vacuo. To the t WO 00/06148 PCT/US99/16962 resulting product was added water (250 mL) and the mixture was stirred in ice bath for 2 hours, then chilled in the refrigerator for 1 hour. The resulting mixture was filtered to give 5.94 g of the title compound.
Example 1 N-2-[4-((3-N,N-dimethylami.nopropyl) carboxamido)phenyl]pro yl 2-propanesulfonamide.
H
wN N O
~ 0 ~H S \

To an ambient temperature solution of 4-(N,N-dimethylamino)butyric acid (0.167 g, 7..0 mmol) in methylene chloride (10 mL) was added oxalyl chloride (0.254 g, 2 mmol) portionwise. Initiation of the reaction was accomplished by the addition of one drop of dimethylformamide. The reaction mixture was stirred for 2 hours at am~~ient temperature. The reaction mixture was then concentrated under vacuum to give an oily product which was subsequently treated with triethylamine (0.200 g, 2 mmol) and th.e product of Preparation 4 (0.256 g, 1 mmol) in methylene chloride (50mL). The reaction mixture was stirred at ambient temperature for 16 hours. The solution was then concentrated under vacuum to yield an oil (0.314 g).
Purification of the oil by chromatotron silica gel chromatography using a 2000 micron.rotor and eluting with a gradient solvent of ethyl acetate/methanol 1:1 and 1%
ammonium hydroxide to methanol/1% ammonium hydroxide afforded the title compound (78 mg) as a clear oil. The NMR
spectrum was consistent with the proposed structure. Ion spray mass spectrum M +1 = 370.4 Analysis calculated for c18H31N3~3s-0.75H20: %C, 56:44; %H, 8.55; N, 10. 97. Found:
%C, 56.47; %H, 8.49; %N, 10.98.

Example 2 N-2-(4-(N,N-dimethylglycinamido)phenyl]propyl 2 propanesulfonamide maleate.
H
.' N N ,I ~ 0 O O
H S
O O HO OH
N,N-Dimethylglycine (0.103 g, 1.0 mMol), oxalyl chloride (1.3 g, 10 mmol), triethylamine (1.01 g, 10 mmol), and the product of Preparation 4 (0.200 g, 0.78 mmol) in methylene chloride (50 mL) were reacted as described in Example 1 to yield an oil (0.187 g). The oil was purified by chromatotron silica gel chromatography using a 1000 micron rotor and eluting with an isocratic solvent of ethyl acetate to yield a clear oil (0.30 g). The NMR spectrum was consistent with the proposed structure. Field absorption mass spectrum: M = 340 This material was reacted with malefic acid to give the title compound (.036 g) as a white solid. m.p. 120°-122°C Analysis calculated for C2pH31N307S-0.5H20: %C, 51.50; oH, 5.65; oN, 9.01. Found: oC, 51.39; oH, 6.47, oN, 8.89.
Example 3 N-2-[4-(aminocarbonylmethoxyacetamido)phenyl]
propyl 2-propanesulfonamide.
H2N O N ~ ~ 0 -N-S
O O H y O
The product of Preparation 4 (0.300 g, 1.17 mmol), aminocarbonylmethoxyacetic acid (0.156 g, 1.17 mmol), 4-dimethylaminopyridine (.036 g; 0.29 mmol), 1-[3-dimethylamino-propyl]-3-ethyl carbodiimide hydrochloride (0.449 mg, 2.34 mmol), and triethylamine (1.0 g, 9.9 mmol) were placed in methylene chloride (25 mL) and stirred overnight under nitrogen at ambient t.=mperature. In the morning, the reaction was diluted with an additional 25 mL
methylene chloride and the organic so:Lution was washed once with water, dried over K2C03, and concentrated under reduced pressure to yield 1.S g. of a semi-solid. Purification was achieved by chromatotron silica gel chromatography using a 4000 micron rotor and eluting with an isocratic solvent of ethyl acetate/methanol 9:1 to yield the title compound (0.080 g) as a clear liquid. The NMR spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 = 372.2 IR shows amide carbonyl stretch at 1690.88 cm t Analysis calculated for C16H25N3OSS: %C, 51.74;
oH, 6.78; oN, 11.31. Found: %C, 51.36; oH, 6.78; oN, 11.00..
Example 4 N-2-[4-(3-methoxycarbonylpropanoyl)amido)-phenyl]propyl 2-propanesulfonamidc=_.
O
" I ~
N O
O _H S

The product of Preparation 4 (0.256 g, 1.0 mmol), mono-methyl succinate (0.132 g, 1.0 mmol), 4-dimethylamino pyridine (.015 mg, 0.12 mmol), 1-[3-dimethylamino-prapyl]-3-ethyl carbodiimide hydrochloride (0.384 g, 2.0 mmol), and triethylamine (0.025 g, 0.25 mmol) were placed in methylene chloride (25 mL) and reacted as described in Example 3 to yield a semi-solid (1.41 g). Purification was achieved by chromatotron silica gel chromatography using a 2000 micron rotor and eluting with an isocratic solvent of methylene chloride/methanol 19:1 to yield the title compound (0.160 g). as a semi-solid. The NMR spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 =

371.2 Analysis calculated for C1-,H26rf205S: %C, 55.12; oH, 7.07; $N, 7.56;
Found: oC, 55.31; oH; 7.20; $N, 7.49.
Example 5 N-2-[4-(4-acetamido)butanoylamido)phenyl]-propyl 2-propanesulfonamide.

~ 0 / _N n H O H_S
O
The product of Preparation 4 ( 0~. f.56 g, 1. 0 mmol, 4-acetamidabutyric acid (0.145 g, 1.O mmol), 4-dimethylamino-pyridine ( . 015 g, 0.12 mmol ) , 1- [3-dirr~ethylaminopropyl ]-3-ethyl carbodiimide hydrochloride (0.384 g, 2.0 mMol), and triethylamine (.025 mg, .25 mmol) were placed in methylene chloride (25 mL) and reacted as described in Example 3 to yield an oil (1.62 g). Purification was achieved by chromatotron silica gel chromatography using a 2000 micron rotor and eluting with an isocratic solvent of ethyl acetate/methanol 29:1 to,yield the title compound (0.118 g) as a clear oil. NMR was consistent with the proposed structure: Ion spray mass spectrum: M+1 = 384.2 Analysis calculated for C18H29N3OqS: oC, 56.32; '~H, 7.56; ~N, 10.95.
Found: oC, 56.64; ~H, 7.62; oN, 11.30.
Example 6 N-2- f4- l4- (t-butoxycarbon~ylamino) -butanovlamido)phenyllprotwl 2-nrc~panesulfonamide O
N ~ ~ 0 O~N n O H S

The product of Preparation 4 (0.256 g, 1.0 mmoi, 4-t-butoxycarbonylaminobutyric acid(0.203 g, 1.0 mmol), 4-. , WO 00/06148 PCT/US99/16962 dimethylaminopyridine (0.15 g, 0.12 mrnol), 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (0.384 g, 2.0 mmol), and triethylamine (.025 g, 0.25 mmol) were placed in methylene chloride (25 mL) and reacted as described in Example 3 to yield an oil. (1.55 g).
Purification was achieved by chromatot:ron silica gel chromatography using a 2000 micron rotor and eluting with an isocratic solvent of methylene chloricle/methanol 19:1 to yield the title compound (0.317 g) a~; a clear oil. The NMR
spectrum was consistent with the proposed structure. Ion spray mass spectrum: M +1 = 442.2 Example 7 N-2-f4-(3-piperidinvlpropanoylamid.o)-phenyllpropyl 2 prooanesulfonamide~
H
1 N / v O
~ __ H S \
O O
The product of Preparation 4 (0.256 g, 1.0 mmol), 3-piperidinylpropionic acid (0.157 g, 1.0 mmol), 4-dimethylaminopyridine (.015 g, .12 mmol), 1-[3-dimethylamino-propyl]-3-ethyl carbodiimide hydrochloride (.384 g, 2.O mmol), and triethylamine (.025 g, 0.25 mmol) were placed in methylene chloride (25 mL) and reacted as described in Example 3 to yield an oil (1.84 g).
Purification. was achieved by chromatot:ron silica gel chromatography using a 2000 micron rotor and eluting with an isocratic solvent of ethyl acetate/methanol 9:1 to yield the title compound (0.280 g) as a clear oil. The NMR
spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 = 396.2 Analysis calculated for 3O C2oH33N3O3S-0.25H20: oC, 59.92: $H, 8.20; $N, 10.48. Found:
oC, 59.97; oH, 8.78 %N, 10.02.

Example 8 N-2-[4-(5-N,N-dimethylamino)pent<~noylamido)phenyl]
propyl 2 -.propanesul f onamide .
N ~ ~ ~ O
O ~...._H_S~
O
The product of Preparation 4 ( 0 . 256 g, 1. 0 mmol ) , 5-N,N-dimethylaminovaleric acid (0.181 nng; 1.0 mmol), 4-dimethylaminopyridine (.015 mg, 0.12 n:~mol), 1-[3-dimethylamino-propyl]-3-ethyl carbodi~_mide hydrochloride (0:384 g, 2.O mmo1), and triethylamine (.050 g, 0.50 mmol) were placed in methylene chloride (25 mL) and reacted as described in Example 3 to yield an oil. (1.77 g).
Purification was achieved by chromatot:ron silica gel chromatography using a 2000 micron rotor and eluting with an isocratic solvent of methylene chloricle/methanol 9:1 to yield the title compound (0.289 g) as a clear oil. The NMR
spectrum was consistent with the proposed structure. Ton spray mass spectrum: M+1 = 389.2 Analysis calculated for C19H33N3~3S-O.5H20 $C, 58. 09; °sH, 8. 67; "sN, 10.95.. Found: ~C, 58.11; oH, 8.67; oN, 11.04.
Example 9 N-2-[4-(3-N-cyclohexylamino)-propanoylamido)phenyl]propyl 2 propanesulfonamidES.
N ~ ~ ~ O
N ~--N-S
y O
The product of Preparation 4 (0.256 g, 1.0 mmol), N-cyclohexyi-j3-alanine (0.171 g, l.O mmol), 4-dimethylamino-pyridine (0.015 g, 0.12 mmol), 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (0.384 g, 2.0 mmol), and triethylamine (0.025 g, 0.25 mmo1) were placed in methylene chloride (25 mL) and reacted as described in Example 3 to yield an oil (1.67 g). Purification was achieved by chromatotron silica geI chromatography using a 2000 micron rotor and eluting with an isocratic solvent of methylene chloride/methanol 9:1 to yield the title compound (0.031 g) as a clear oil. NMR was consistent with the proposed structure. Ion spray mass spectrum: M~+1 = 410.
Example 10 N-2- [ 4- (2-ethoxy) acetamido ) phenyl ] propyl 2-propanesul fonami<ie .
/'~O~ N_S
O H n~
O
The product of Preparation 4 (0.300 g, 1.17 mmol, 2-ethoxyacetic acid (0.122 g), 1.17 mmol}, 4-dimethylamino-pyridine (0.011 g, 0.09 mmol), 1-[3-di:methylaminopropylJ-3-ethyl carbodiimide hydrochloride (0.269 g, 1.4 mmol), and triethylamine (0.300 g, 3.O mmo1) were placed in methylene chloride (25 mL) and stirred overnight under nitrogen at ambient temperature. In the morning, the reaction mixture was diluted with an additional 25 mL methylene chloride and the organic solution was washed once with water, dried over K2C03, and concentrated under reduced pressure to yield a semi-solid (1.41 g). Purification was achieved by chromatotron silica gel chromatography using a 4000 micron rotor and eluting with an isocratic solvent of methylene chloride/ethyl acetate 1:1 to yield thE~ title compound (0.060 g) as a white solid m.p. lI3°-116°C. The NMR
spectrum was consistent with the propo:~ed structure. Ion spray mass spectrum: M+1 343.1 Analysis calculated for C16H2sN209S: %C, 56.12; %H, 7.65; %N, 8.18. Found: %C, 56.21;
%H, 7 . 61; %N, 8 .16 .

WO 00/06148 . PCT/US99/16962 Example 11 N-2-[4-(2-methoxyacetamido)phenyl]propyl 2-propanesulfonamide.
N ~ ~ O
w0 " ~H_S~

The product of Preparation 4 (0.300 g, 1.17 mmol), 2-methoxyacetic acid (0.106 g, 1.17 mmol), 4-dimethylamino-pyridine (0.011 g, 0.09 mmol), 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (0.269 g, 1.4 mmol), and triethylamine (0.300 g, 3.0 mmol) were placed in methy.lene chloride (10 mL) and stirred overnight under nitrogen at ambient temperature. In the morning, the reaction mixture was diluted with an additional 25 mL methylene chloride and the organic solution was washed once with water, dried over K2C03, and concentrated under reduced pressure to yield a semi-solid (1.71 g). Purification was achieved by chromatotron silica gel chromatography using a 4000 micron rotor and eluting with an isocratic solvent of methylene chloride/ethyl acetate 9:1 to yield the title compound (72 mg) as a brown oil. The NMR spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 =
329.2 Analysis calculated for C15H29N209S-1H20: ~C, 52.03;
oH, 7.57; oN, 8.08. Found: ~C, 52.35; ~H, 7.72; ~N, 7.76.
Example 12 N-2-[4-(2-butoxyacetamido)ph.enyl]propyl 2-propanesulfonamid.e.
n H_S

' ' WO 00/06148 PCTIUS99/16962 The product of Preparation 4 (0.;300 g, 1.17 mmol), 2-butoxyacetic acid (0.155 g, 1.17 mmol;l, 4-dimethylamino-pyridine ( 0 . 011, g, 0 . 09 mmol ) , 1- [ 3-d_Lmethylamino-propyl ]-3-ethyl carbodiimide hydrochloride (0.2E59 mg, 1.4 mmol), and triethylamine (0.300 mg, 3.O mmol) were placed in methylene chloride (10 mL) and stirred overnight under nitrogen at ambient temperature. In the morning, the reaction mixture was diluted with an additional 25 mL methylene chloride and the organic solution was washed once with water, dried over KZC03, and concentrated under reduced pressure to yield a semi-solid (1.06 g). Purification was achieved by chromatotron silica gel chromatography using a 4000 micron rotor and eluting with an isocratic solvent of methylene chloride/ethyl acetate 3:2 to yield th.e title compound (0.121 g) as a clear oil. The NMR spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 =
372.2 Analysis calculated for C,8H3oN209S: oC, 52.03; oH, 7.57; oN, 8.08.
Found: oC, 52.35; oH, 7:72; ~N, 7.76.
Example 13 N-2- [ 4- ( 1- ( 4-methyl ) piperazinyl ) ac:etamido ) phenyl ]
propyl 2-propanesulfonamide.
N ~ ~ O
~N~ ~IH_S~
-~N~ ~
The product of Preparation 5 (0.1.50 g, 0.59 mmol) and N-methylpiperazine (0.065 g, 1.2 ey.) were placed into toluene (20 mL) and stirred at re:flux under nitrogen for 2 hours. The reaction mixture was then cooled to ambient temperature and diluted with 50 mL of 1N sodium hydroxide and 50 mL of ethyl acetate. The organic layer was separated, washed once with water, dried over K2C03, _47-and concentrated under reduced pressuz:e to yield an oil (117 mg). Purification was achieved by chromatotron silica gel chromatography using a 100C) micron rotor and eluting with an isocratic solvent of methylene chloride/methanol 9:1 to yield the title compound (0.074 g) as a white solid. m.p. 134°-136°C. The NMR spectrum was consistent with the proposed strucaure. Ion spray mass spectrum: M+1 = 379.2 Example 14 N-2-f4-tl-piperidinylacetamido) ohenyllpropyl 2-propanesulfonamide O
n N ~H_S~
O O
The product of Preparation 5 (0.150 g, 0.59 mmol) and piperidine (0.55 g, 1.1 eq.) were :placed into toluene (20 mL) and reacted as described in Example 13 to yield a clear oil (0.175 g)a Purification was achieved by chromatatron silica gel chromatography using a 1000 micron rotor and eluting with an isocratic solvent of ethyl acetate to yield the title compound (0.120 g) as a white solid. m.p. 139°-141°C. The NMR spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 = 382 . 4 Analysis calculated for C19H31N3O3S
%C, 59.81; %H, 8.19; %N, 11.01. Found: %C, 59.51; %H, 8.29; %N, 11.06.

Example 15 N-2-[4-(1-(4-N,N-dimethylamino)pipe:ridinyl)acetamido (phenyl]propyl 2-propanesu~Lfonamide.
N ~ ~ \ 0 N II ~~N_S
O H y 'w N O
The product of Preparation 5 (O.:L50 g, 0.59 mmol) and 4-(N,N-dimethylamino)piperidine (0.083 g, 1.1 eq.) were placed into toluene (20 mL) and reacted as described in Example 13 to yield an oil (0.173 c~). Purification was achieved by chromatotron silica gel chromatography using a 1000 micron rotor and eluting with a gradient solvent of methanol to methanol/1o ammonium hydroxide to yield the title compound (0.104 g) as a viscous oil. The NMR spectrum was consistent with the proposed structure:
Ton spray mass spectrum: M+1 = 425.3 Analysis calculated for C21H3~N9035-0.5H20: oC, 58.16; oH, 8.60; oN, 12.92. Found: oC, 57.98; oH, 8.61; ~N, 12.76.
Example 16 N-2-[4-(propylaminoacetamido)phenyl]propyl 2-propanesulfonamide.
H
~N N ~
H HTS \
O O
The product of Preparation 5 (0.150 g, 0.59 mmol) and propylamine (50 mg, 1.1 eq.) were placed in toluene (20 mL) and reacted as described in Example 13 to yield an oil (0.179 g). Purification was achieved by chromatotron silica gel chromatography using a 2000 rotor WO 00/06148 PCT/C)S99/16962 and eluting with an isocratic solvent of methylene chlorida/methanol 9:1 to yield the title compound 0.089 g as a clear oil. The NMR spectrum was consistent with the proposed structure. Ion spray mass spectrum: M+1 =
356.4 Analysis calculated for Cl~H2gN303S-1/2 H20: oC, 56.01; oH, 8.29; oN, 11.53.
Found: oC, 55.91; $H, 7.99; oN, 11.60.
Example 17 N-2-(4-(4-(2-(1- yrrolidino)ethoxy)phenyl)phenyl)propyl 2-propanesulfonamide hydrochloride.
HCI
H ~t O
To a stirred solution of 3.05g (1:1.3 mmol) of 1-[2-(4-bromophenoxy)ethylpyrrolidine in 50mL o f anhydrous THF under N2 was added 5.OmL (12.5mmo1) of n-BuLi. at -70 °C. The mixture was stirred for 30 minutes and 1.5g (14.2 mmol) of B(OCH3)3 was added dropwise. Stirring was continued for 1.5 h. at -2 to 5°C. The reaction mixture was then quenched with a saturated solution. of ammonium chlor_Lde. The THF layer was dried(MgS09), filtered and evaporated in vacuo. The residual glass was dissolved in 50mL of ethylene glycol dimethyl ether (DME) followed by addition of 3.Ei8 g (12.0 mmol) of N-2-(4-bromophenyl)propyl-2-propanesulfonamide, 0.3908 (0.3~
mmol) of palladium tetrakis, 11.3mL (20. 6 mmol) of 2M Na2C03 and 2.0 mL (26.8 mmol) of n-propyl alcohol respectively. The resulting mixture was heated and stirred under N2 at reflux for 6h. The reaction was cooled to ambient temperature, diluted with 100mL of EtOAc and filtered through celite.
Evaporation of the filtrate in vacuo followed by chromatography eluting with loo CH30H-90~CH2C12 gave the desired compound (1.79g) as a light brown oil. Addition of methanolic HC1 and recrystallization from CH30H-EtOAc gave the title compound, mp 172-173° C. Ana:Lysis calculated for C2aH3aN2O3S . HC1-0 . 33H20: C, 60 . 93; H, 7 . :i9; N, 5 . 92 . Found:
C,60.85; H, 7.34; N, 6.02.
Example .L 8 N-2- ( 4- ( 4- ( 2- (N, N-dimethylamino ) ethoxy) phenyl ) phenyl ) propyl 2-propanesulfonamide hydrochloride.
O ~ ~ ~ ~ ~ HCi _.N~ ~ ~N_S
H ~~
O
To a stirred solution of 4-(N,N-d:imethylaminoethoxy)-phenyl bromide (1.0 g, 4.10 mmol) in 20 mL of THF under N2 was added 2.1 mL (5.33 mmol) of a 2.5 M solution of n-FuLi at -78°C. The mixture was stirred for 30 minutes and 0.56 mL (4.92' mmol) of trimethyl borate was added dropwise.
Stirring was continued for 1.5 hours at. -2 to 5°C then the reaction mixture was concentrated in va_cuo. The resulting residual solid was dissolved in 20 mL of of ethylene glycol dimethyl ether (DME) followed by addition of 1.0 g (3.12 mmol) the product of Preparation 8 0.14 g (0.12 mmol) of tetrakis (triphenylphosphine)palladium~;0), 3. I2 mL (6.24 mmol ) of 2 M Na2C03 and 0 . 47 mL ( 6 . 24 mmol ) of n-propyl alcohol,,respectively. The resulting mixture was heated at reflux while stirring under N2 for 6 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with 30 mL of ethyl acetate and filtered through Celite.
Evaporation of the filtrate in vacuo followed by chromatography, eluting with 95:5 methylene chloride/methanol gave 0.22 g of the desired compound as a yellow oil. The residue was dissolved in ether and a saturated solution of HCl in methanol was added dropwise until precipitation of a solid was obi>erved. The ether was decanted off and the resulting solid was triturated several times with ethyl acetate to afford thE: title compound as a white solid. 1H NMR (400 MHz, CDC13) : ~> 1.29 (9H, m) , 2.93 {6H, s), 2.94-3.16 {2H, m), 3.19-3.39 (2H, m), 2.44 (2H, t), 4. 00 (1H, t) , 4.71 (2H, t) , 6. 91-7.52' (8H, m) , 12.93 (1H, Example 19 N-2-{4-(4-(2-hydroxy)ethoxy)phenyl)phenyl)propyl 2-propanesulfonamide.
O / \ / \ ~ O
HO~ ~"~ ~N S
H ii O
2--(4-bromophenoxy)ethanol (0.50 g, 2.30 mmol) was dissolved in 15 mL of THF and stirred at 0 °C under N2:
0.10 8 (2.53 mmol) of a 600 oil dispersion of sodium hydride was added in small portions and the mixture was stirred for 30 min. then cooled to -78 °C followed by the addition of 1.3 mL {2.53 mmol) of a 2.5 M solution of n-BuLi. The mixture was stirred for 30 minutes and 0.58 mL (2.53 mmol) of triisopropyl borate was added dropw:ise. Stirring was continued for 1.5 hours at -2 to 5 °C then the reaction mixture was quenched eaith a 1.0 M_ salui~ion of HC1. The layers were separated and the organic phase was dried {MgS09) and concentrated. The resulting oil was dissolved in 10 mL of of ethylene glycol dimethyl el:her {DME) followed by addition of 0.51 g (1. G0 mmol) of the product of Preparation 8, 0.074 g (0.064 mmol) of tetrakis (triphenylphosphine)-palladium(0), 1.60 mL {3.20 mmol)of 2 M Na2C03 and 0.24 mL
(3.20 mmol) of n-propyl alcohol, respecaively. The resulting mixture was heated at reflux: while stirring under N2 for 8 hours. The reaction mixture 'was allowed to cool to ambient temperature. 5 mL of H20 were added and the layers were separated. The aqueous layer was extracted with ether and the organics were combined, washed with saturated NaCl and H20, dried (MgS04) and concentrates! to a brown oil.
Chromatography, eluting with 99:1 methylene chloride/methanol gave 0.07 g (20 0) of a light yellow solid. Recrystallization from hexanes/methylene chloride yielded the desired compound. 'H NMR (400 MHz, CDC13): ~ 1.23 (9H, m), 2.16 (1H, s), 2.96-3.12 (2H, :m), 3.21-3.39 (2H, m), 3.97 (2H, t), 4.11 (2H, t), 6.96-7.48 (8H, m); LRMS (ES-) 376.4 M-H; Anal. Calculated for C2oH2-,N~~O9: %C, 63.63; oH, 7.21; oN, 3.71. Found oC, 63.70; oH, 7.15; $N, 3.96.
Example 20 N-2- [ 4- ( 2- (N, N-dimethylamino ) ethoxy) phenyl ] propyl 2-propanesulfonamioLe.
O ~ ~ o ~ n ~N H S
zo ~ O
The product of Preparation 12 (0.250 g, 0.7 mmol) was dissolved in dimethylformamide and sodium hydride (0.031 g, 0.77 mmo1) was added. After 15 minutes, 2-N'N-dimethylaminoethyl chloride hydrochloride (0.126 g, 0.77 mmol), potassium carbonate (0.128 g, 0.93 mmol) and potassium iodide (0.035 g, 0.21 mmol) were added to the reaction and the mixture was stirred at 65°C for 2 hours.
The reaction mixture was partitioned between dichloromethane and water. The organic was washed with. brine, dried over sadium sulfate and concentrated in vacuo. Chromatography Si02, 5~ methanol/dichloromethane) gave 0.101 g (34~) of the ' ' WO 00/0614$ PCT/US99/16962 pure product which was dissolved in 2 mL of the dichloromethane: TFA (1:1). The mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was partitioned between dichloromethane arid water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 0.077 g (910) of the title compound.
Electrospray Mass Spectrum: M = 329.3 Analysis calculated for C,6H28N203SØ25Fi20: oC, 57.71; oH, 8.63; %N, 8.41. Found: oC, 57.84; oH:, 8.37; oN, 8.44.
Example 21 N-2-[4-(3-(N,N-dimethylamino)prapoxy)phenyl]propyl 2-propanesulfonamide.
O / \ O
N~ H_S
~ 0 The title compound was prepared from the product of Preparation 12 and 3-N,N-dimethylaminopropyl chloride hydrochloride as described in Example 20. Electrospray Mass Spectrum: M = 343.1 Analysis calculated for Cl,H3oN203S-0.5H20: oC, 58.84; oH, 8.86; oN, 8.0i'. Found: $C, 59.00;
%H, 8.66; %N, 7.50.
Example 22 N-2- ( [ 4- ( 2- ( 1-piperidinyl ) eth.oxy) phenyl ] propyl 2-propanesulfonamid.e.
O ~ \ 0 _o N~ ~Fi S \
O

The title compound was prepared from the product of Preparation 12 and 2-(1-piperidinyl)et;hyl chloride as described in Example 20. Electrospray Mass Spectrum: M =
369.1 Analysis calculated for C19H32N2O3S: %C, 61.92; oH, 8.75;
%N, 7.60. Found: sC, 61.98; oH, 8.27; ~N, 6.99.
Example 23 N-2-[4-(3-(1-piperidin 1)propoxy)phenyl]propyl 2 propanesulfonamide.
O ~ ~ O
NS
H O
The title compound was prepared from the product of Preparation 12 and 3-(1-piperidinyl)propyl chloride as described in Example 20. Electrospray Mass Spectrum: M
383 . 4 . Analysis calculated for C2oH39N2O3S : oC, 61 . 92; oH, 8.75; oN, 7.60. Found: ~C, 61.98; °sH,, 8.27; %N, 6.99.
Example 24 N-2-[4-(4-chlorophenoxymethyl)ox.y)phenyl]propyl 2-propanesulfanami<ie O ~ ~ O
O--.~ _ n ' H_S
O
CI
The product of Preparation 12 (0.2:50 g, 0.7 mmol) was dissolved in dimethylformamide and sodium hydride (0.034 g, 0.84 mmol) was added. After 30 minutes a-4-dichloroanisole (0.136 g, 0.77 mmol) and potassium iodide (0.025 g, 0.14 mmol) were added to the reaction and i~he mixture was stirred at 65°C for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic was washed with brine, dried over sodium sulfate and concentrated. in vacuo. The crude product was dissolved in 2 mL of the dichloromethane: TFA (1:1). The mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was partitioned between dichloromethane and water. The organic was dried over sodium sulfate and concentrated in vacuo to give 0.172 g (62%) of the title compound. Electrospray Mass Spectrum: M = 396. Analysis calculated far C19H29C1NOQS: %C, 57.35; %H, 6.08; oN, 3.52. Found: %C, 57.90; %H; 6.10; %N, 3.56.
Example 25 N-2-[4-(2-phenoxyethyl)oxy)phenyl]propyl 2-propanesulfonamide.
O / ~ O
/ \ o~ -H-s---~

The title compound was prepared from the product of Preparation 12 and phenoxyethyl chloride as described in Example 24. Electrospray Mass Spectrum: M = 377.5 Analysis calculated for C2oH2,N04S: %C, 63.63; %H, 7.21;
%N, 3.71. Found: %C, 63.70; %H, 7.46; %N, 3.85.

Example 26 N-2- [ 4- ( 2- ( 4-acetamido ) phenyloxyei~hoxy) phenyl }propyl 2-propanesulfonamide.
p / ~ O
O~ H
O
O
4-Acetamidophenol (0.091 g, 0.6 rcumol) was dissolved in 3 mL dimethylformamide and sodium hydride (0.024 g, 0.75 mmol) was added. After 30 minutes the product of Preparation 13 (0.250 g, 0.6 mmol) and. potassium iodide (0.025 g, 0.15 mmol) were added to the reaction and the mixture was stirred at 65°C for 4 hour,. The reaction mixture was partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography (Si02, 50 methanol/dichloromethane) gave 0.164 g (510) of the pure product. The resulted product was dissolved in 2 mL of the dichloromethane: TFA (1:1). The mixture was stirred at ambient temperature for 1 minute. The .reaction mixture was then partitioned between dichlorametha:c~e and water. The organic was washed with brine, dried over sodium sulfate and concentrated .in vacuo to give 0.090 g (740) of the title compound. Electrospray Mass Spectrum: M = 435.4 Analysis calculated for C22H3oN205S: oC,, 60.81; ~H, 6.96;
oN, 6.45. Found: °sC, 60.84; oH, 7.16; oN, 6.72.

a WO 00/06148 PCT/US99/16962 Example 27 N-2-[4-(2-(3-acetamido)phenyloxyei:hoxy)phenyl]propyl 2-propanesulfonamide.
O H
/ N O / \ O
/ \ O~ H S
O
The title compound was prepared from the product of Preparation 13 and 3-acetamidophenol a.s described in Example 26. Electrospray Mass Spectrum: 435.4 Analysis calculated for C22H3oN205S : %C, 60. 81; %H, 6. 96; %N, 6. 45. Found: %C, 60.29; %H, 6.88; %N, 6.36 Example 28 N-2-[4-((2-acetamido)phenyloxyeth.oxy)phenyl]propyl 2-propanesulfonamide.
-,_O
-- ~N H O / \ O
/ \ o'~ -H-sw--C

The title compound was prepared from the product of Preparation 13 and 2-acetamidophenol a~s described in Example 26. Electrospray Mass Spectrum: 435.3.
Analysis calculated for C22H3oN20sS-0.1C1?3COOH: %C, 59.79; %H, 6.80; %N, 6.28. Found: %C, 59.46; %H, 0.49; %N, 6.24.
Example 29 N-2- (4- (2-phenoxyethoxy) -phenyl) -propyl-2-propanesulfonamide.
/ \
/ \ ~ ~-N_s O H y O

WO 00106148 PCT/US99/~69b2 To a stirred mixture of N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide (0.250 g,.70 mmol) in dry dimethylformamide (4 mLy was added sodium hydride (0.062 g, 0.87 mmol) under nitrogen. The resulting mixture was stirred 30 minutes at ambient temperature or until hydrogen gas evolution had ceased'. Next, (3-chiorophenetole (O.i20 g, 0.77 mmol) and sodium iodide (0.042 g, 0.25 mmol) are added and the resulting mixture was heated to 65°C for 12 h. The resulting mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water (2 X 20 mL) and brine (1 X 20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gavE~ 0.250 g (75Q) of the protected sulfonamide. To a stirred mixture of dichloromethane: trifluoroacetic acid (2 mL, 1:1) was added the protected sulfonamde (0.220 g, 0.42 mmol) under nitrogen. The resulting mixture was stirred at ambient temperature for 4 h. The mixture was partitioned between dichloromethane and loo aqueous potassium carbonate. The organic layer was washed with brine (1. X 20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in tracuo gives 0.166 g (96%) of the pure title compound.
Mass Spectrum: MS +' = 378.5 Analysis for CZOH2-,N04S
Theory: C, 63.63; H, 7.21; N, 3.71.
Found: C, 63.70; H, 7.46; N, 3.85.

' WO 00/06148 PCTIUS99/16962 Example 30 Specific Preparation of N-2-(4-(2-(2-acetamidophenoxy) ethoxy)-phenyl)-propyl-2-prop;anesulfonamide.

O / \ p O/"'~ H_S
~__ / \ n O
To a stirred mixture of 2-hydroxyacetanilide (0.091 g, 0.60 mmol) in dry dimethylformamide (3 mL) was added sodium hydride.(0.030 g, 0.75 mmol) under nitrogen. The resulting mixture was stirred 30 minutes at ambient temperature or until hydrogen gas evolution had ceased. Next, N-tertbutoxyacetyl-2-[(4-(2-chloroethoxy)-phenyl)-propyl)-2-propanesulfonamide (0.250 g, 0.60 mmol.) and sodium iodide (0.025 g, 0.15 mmolj are added and the resulting mixture is heated to 65°C for 12 h. The re~"1 t-; "~n m; v;-",-o ,..-,~ ......, ..a and partitioned between ethyl acetate and water. The organic layer was washed with water (2 X 20 mL) and brine (1 X 20 m.L), dried over magnesium sulfate, and filtered.
Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 0.100 g (310) of the protected sulfonamide. To a stirred mixture of dichloromethane:trifluoroacetic acid (2 mL, 1:1) was added the protected sulfonamde (0.100 g, 0.19 mmol) under nitrogen. The resulting mixture was stirred at ambient temperature for 4 h. The mixture was partitioned between dichloromethane and loo aqueoua potassium carbonate.
The organic layer was washed with brim' (1 X 20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 0:080 g (980) of the pure title compound .
Mass Spectrum: MS +~ = 435.3 ' WO OOJ06I48 PCTlUS99J16962 Example 31 N-2-(4-(2-(2-fluorophenoxy)-ethoxy)-phenyl)-propyl-2-propanesulfonamide.
F O / \ O
/ \ ~ ~~
O ~H~S~

The title compound was prepared from the product of preparation 14 and 2-fluorophenol in a manner analogous to Example 30.
Mass Spectrum: MS +1 - 396.1 Analysis for C2oH26FN04S
Theory: C, 60.74; H, 6.63; N, 3.54.
Found: C, 60.f3; H, 6.71; N, 3.44.
Example 32 N-2- ( 4- ( 2- ( 3-fluoro henoxy) -ethoxy) -phenyl ) -propyl-2 propanesulfonamide F / \
/ \ o~ _N_s~
H
The title compound was prepared from the product of Preparation 14 and 3-fluorophenol in a manner analogous to Example 30.
Mass Spectrum: MS +1 - 396.0 Example 33 N-2-(4-(2-(4-fluorophenoxy)-ethoxy~-phenyl)-propyl-2 propanesulfonamide.
O / \ ~ O
/ \ O~ ~H~S~
~
The title compound was prepared from the product of Preparation 14 and 4-fluorophenol in a manner analogous to Example 30.
Mass Spectrum: MS +' - 396.1 Analysis for C~oH26FNO9S
Theory: C, 60.74; H, 6.63; N, 3.54.
Found: C, 60.85; H, 6.60; N, 3.79.
Example 34 N-2- (4- (2- (3-trifluorometh~rlphenoxy) -et:hoxy~phenyl) -uropvl 2-propanesulfonamide FsC O / \ O
n / \ ..-H_S
O
The title compound was prepared from the product of Preparation 14 and 3-hydroxybenzotrifluoride in a manner analogous to Example 30.
Mass Spectrum: MS -1 - 444.3 Analysis for C21H2sF3NO9S + .8H20 Theory: C, 54.84; H, 6.05; N, 3.04.
Found: C, 54.44; H, 6.28; N, 3.02.

WO 00/06148 PCT/US99/1~962 Example 35 N-2-(4-(2-(4-trifluoromethylphenoxy}-ethoxy}-phenyl}-propyl-2-propanesulfonamide.
o / \ O
~ n F3C / \ O H-S
The title compound was prepared from the product of Preparation 14 and 4-hydroxybenzotrifluoride in a manner analogous to Example 30.
Mass Spectrum: MS -; - 444.2 Analysis for C21H26F3N04S
Theory: C, 56.62; H, 5.88; N, 3.14.
Found: C, 56.85; H, 5.94; N, 3.32.
Example 36 N-2- (4- (2- (2, 3-difluorophenoxy} -ethox:y) -phenyl) -propyl-2-propanesulfonamide.
F F O / \ p / \ n 0~ _H_S~
O
The title compound was prepared from the product of Preparation 14 and 2,3-difluorophenol in a manner analogous to Example 30.
Mass Spectrum: MS +1 = 414:2 Analysis for C2flH25F2NO9S
Theory: C, 58.10; H, 6.09; N, 3.39.
Found: C, 58.17; H, 6.39; N, 3.45.

' ' WO 00/06148 PCT/US99116962 Example 37 N-2-(4-(2-(2-cyanophenoxy)-ethoxy)-phenyl)-propyl-2-propanesulfonamide.
N
/ \
n / \ o~' H-S
~
The title compound was prepared from the product.of Preparation 14 and 2-cyanophenol in a :manner analogous to Example 30.
Mass Spectrum: MS +1 - 403.4 Analysis for CzlHz6N2OqS + .25H20 Theory: C, 61.97; H, 6.56; N, 6.88.
Found: C, 61.66; H, 6.54; N, 6.61.
Example 38 N-2- (4- (2- (3-cyanophenoxy) -ethoxy) ~-phenyl) -propyl-2 propanesulfonamide:.
N
\\ O / \ , 0 n O~ H_S
O
The title compound was prepared from the product of Preparation 14 and 3-cyanophenol in a manner analogous to Example 30.
Mass Spectrum: MS +1 = 403.4 Analysis for CzlHzsN209S
Theory: C, 62.66; H, 6.51; N, 6.96.
Found: C, 62.56; H, 6.39; N, 6.76.

Example 39 N-2-(4-(2-(4-cyanophenoxy)-ethox~-phenyl)-propyl-2-propanesulfonamide.
O / \ O
N- ~ ~ O~ H-S
O
The title compound was prepared from the product of Preparation 14 and 4-cyanophenol in a :manner analogous to Example 30.
Mass Spectrum: MS +1 - 403.4 Example 40 N-2-[(4-(2-(2-chlorophenoxy)-ethoxy)-phenyl)-pro 1]-2-pY
propanesulfonamide~.
Ci o / \ o / \ o~ N s Ho The title compound was prepared from the product of Preparation 14 and 2-cyanophenol in a manner analogous to Example 30.
Mass Spectrum: MS +1 - 412.1 Example 41 N-2-(4-(2-(2-methoxyphenoxy)-ethoxy)-phenyl)-propyl-2-propanesulfonamide.
O O / \ O
0~ -H_S
\ n The title compound was prepared fz:om the product of Preparation 14 and guaiacol in a manner. analogous to Example 30.
Mass Spectrum: MS +1 = 408.4 WO OO/Ob148 PCT/US99/I6962 Example 42 N-2- [ ( 4- ( 2- ( 2-fluorothiophenoxy) -etho~,y) -phenyl ) -propyl ] -2 propanesulfonamide.
F o / \ o / \ S~ _ _S~

The title compound was prepared from the product of Preparation l4 and 2-fluorothiophenol .in a manner analogous to Example 30.
Mass Spectrum: MS -1 - 410.3 Analysis for C2oH26FNOS2 + .3H20 Theory: C, 57.61; H, x.43; N, 3.36.
Found: C, 57.23; H, 6.75; N, 3.33.
Example 43 N-2- [ (4- (2- (thiophenoxy) -ethoxy) -phenyl) -pro yl] -2 propanesulfonamide.
0 / \ 0 / \ S

The title compound was prepared from the product of Preparation 14 and benzenephenol in a manner analogous to Example 30.
Mass Spectrum: MS -' = 392.2 WO 00/06148 PCTfUS99/16962 Example 44 N-2-(4-(2-(3-pyridyloxy)-ethoxy)-phenyl)-propyl-2-propanesul fonamidE~
o / \ o \-\ O~ H S
p The title compound was prepared from the product of Preparation 14 and 3-hydroxypyridine in a manner analogous to Example 30.
Mass Spectrum: MS +' = 379.5 Analysis for C1gH26N2~4S
Theory: C, 60.29; H, 6.92; N, 7.40.
Found: C, 60.04; H, 7.14; N, 7.15.
Example 45 N-2-(4-(2-(N'-2-pyridinone)-ethoxy)-phenyl)-propyl-2-propanesulfonamide.
O O / \ O
N~ IH S \

The title compound was prepared from the product of Preparation 14 and 2-hydroxypyridine in a manner analogous to Example 30.
Mass Spectrum: MS +1 - 379.4 Analysis for C19H26N2O4S + .15H20 Theory: C, 59.$C; H, 6.95; N, 7.35.
Found: C, 59.50; H, 6.97; N, 7.07.

Example 46 N-2-(4-(2-(2-pyrimidyloxy)-ethoxy)-phenyl)-propyl-2-propanesul fonamidE~ .
n / N O/"J -H_S
O
-N
The title compound was prepared from the product of Preparation 14 and 2-hydroxypyridine in a manner analogous to Example 30.
Mass Spectrum: MS +1 - 380.4 Analysis for C18Hz5N309S
Theory: C, 56.97; H, 6.64; N, 11.07.
Found: C, 57.16; H, 6.72; N, 10.93.
Example 47 N-2- (4- (2- (methoxy) -ethoxy) -phenyl) -propyl-2 propanesulfonamide.
O / ~ O
-O/~ In-!_S~
O
The title compound was prepared from N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide [the product of Preparation 12~ and 2-bromoethylmethylether in a manner analogous to Example 29.
Mass Spectrum: MS +1 - 316.1 Analysis for C1gH25N~4s + .15H20 Theory: C, 56.63; H, 8.02; N, 4.40.
Found: C, 56.64; H, 7.62; N, 4.56.

WO 00/06148 PCT/US9911b962 Example 48 N-2- ( 4- (2- ( ethoxy) -ethoxy) -phenyl ) -propyl-2 propanesul fonamidE~ .
/ ~
O
/"" 0 The title compound was prepared from N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide [the product of Preparation 12] and 2-bromoethylethylether in a manner analogous to Example 29.
Mass Spectrum: MS +2 - 330.2 Analysis for C16H2~NOqS
Theory: C, 58.33; H, 8.26; N, 4.25.
Found: C, 58.05; H, 8.15; N, 4.28.
Example 49 N-2-(4-(2-(2-methoxyethoxy)-ethoxy)-phenyl)-propyl-2-propanesulfonamide.
o / \ ' o O/'~ ~N_S~
Of H
~
The title compound was prepared from N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide [the product of Preparation 12] and 1-bromo-2-(2-methoxyethoxy)ethane in a manner analogous to Example 29.
Mass Spectrum: M5 +1 = 360.2 _59_ Example 50 N-2- { 4- ( 3- (phenoxy) -propoxy) -phenyl ) -propyl-2-propanesulfonamide.
o / \ o .
O_/ ~ H
O
The title compound was prepared from N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide {the product of Preparation 12] and 3-bromopropylphenylether in a manner analogous to Example 29.
Mass Spectrum: MS -' = 390.3 Example 5I
N-2-(4-(3-(phenoxy)-butoxy)-phenyl)-propyl-2-propane sul f onami d~; .
O / \ O
N-S-/ \ H p O
The title compound was prepared from N-tertbutoxyacetyl-2-(4-hydroxyphenyl)propyl-2-propanesulfonamide {the product of Preparation 12] and 4-phenoxybutylbromide in a manner analogous to Example 29.
Mass Spectrum: MS -1 = 404.5 Analysis for C22H31NO4S
Theory: C, 65.16; H, 7.70; N, 3.45.
Found: C, 65.45; H, 7.83; N, 3.62.

' ' WO 00106148 PCT/US99/16962 Example 52 N-2-(4-(4-(2-acetoxyethyl)phenoxy)phenyl)propyl-2 propanesulfonamid~e.
~\ / ' O
p V n O~ H S
O
N-2- ( 4- ( 4- (2-hydroxy) ethoxy) phenyl ) phenyl ) propyl 2-propanesulfonamide (0.10 g, 0.27 mmol, prepared in example 19) was combined with 4-dimethylaminop~yridine (0.003 g, 0.027 mmol) in dry acetonitrile (3 mL). Acetyl chloride (23 ~L, 0.32 mmol) was added and the reaction was stirred at room temperature under N2 for 24 h. The reaction mixture was concentrated to a yellow foam which was dissolved in CH2C12 and washed with 1 M HC1, saturated NaHC03, dried (MgS09 ) and concentrated to a white crystalline solid.
LRMS (ES-) : 418 . 3 (M-1 ) Anal . Calc' d for C22H2gNS05: C 62.98, H 6. 97, N 3.34; Found C
63.14, H 6.85, N 3.27.
Example 53 N-2- ( 4- ( 4- ( 2- (N-phenylcarbamoyl ) ethyl ) phenoxy) prbpyl-2-propanesulfonamide.
O / ~ / ~ O
__ i I
O ~ ~H_S~
O
N
H
N-2- ( 4- ( 4- ( 2-hydroxy) ethoxy) phenyl ) phenyl ) propyl 2-propanesulfonamide (0.05 g, 0.13 mmol, prepared in example 19) and phenylisocyanate (14.0 ~.L, 0.13 mmol) were combined in dry CH2C12 and heated at 40°C for 3 h. while stirring under N2 then cooled to room temperature and stirred ' ° W4 00106148 PCT/US99/16962 overnight. The reaction mixture was t:oncentrated toa brown oil which was purified by chromatotrorr (1 mm plate, Harrison Research Inc., Palo Alto, California) eluting with 1:4 (v/v) ethyl acetate/hexanes to give 0.065 g {1000) of the title compound as a white solid.
1HNMR (400 MHz, CDC13): 8 1.29 (9H, m), 2.94-3.14 (2H, m), 3.19-3.40 (2H, m), 4.08 (1H, t), 4.22 (2H, t), 4.57 {2H, t), 6.82-7.56 (13H, m}
LRMS (ES+) : 497.2 {M+1) LRMS {ES') : 495.2 (M-1) Example 54 N-2- ( 4- ( 4- ( 2- (N-ethylcarbamoyl ) ethyl ) phenoxy) propyl-2 propanesulfonamide.
O ~ ~ ~ ~ O
O
O~ H-S--<
O
N
The title compound was prepared from nf-2- (4- (4- (2-hydroxy)ethoxy)phenyl)phenyl)propyl 2-~propanesulfonamide (prepared in example 19) and ethyl isc~cyanate as described in Example 53. Purification (30o ethyl acetate/70o hexanes) yielded 0.053 g (920) of product as a white solid.
1HNMR (400 MHz, CDC13) : 8 1.22 (9H, m) , 2. 87-3.09 (2H, m) , 3.18 (3H, m), 3.32 (1H, m), 3.80 (1H, t), 4.17 (2H, t), 4.39 (2H, t) , 4. 63 (1H, br. s) , 6. 94 (2H, dl) , 7.20 (2H, d) , 7.42 ( 4H~ m) .
LRMS (ESA) : 449.1 (M+1) LRMS (ES-) : 447.2 (M-1) ~ WO 00/06148 PCT/US99116962 Example 55 N-2- ( 4- ( 4- ( 2- ( 0-methanesul fonyl ) ethyl ) phenoxy) propyl-2 propanesulfonamide.
o / \ ~-.\
O ~ n -S-O~ H~S
O O
Triethylamine (138.0 ~L, 0.99 mmol) was added dropwise to a solution of N-2-(4-(4-(2-hydroxy)ethoxy)phenyl)phenyl)propyl 2-~propanesulfonamide (prepared in example 19) in dry CH2C12 (6 mL) at room temperature while stirring under N2. .After 15 min., methanesulfonyl chloride (61.0 ~L, 0.'T9 mmol) was added dropwise and the reaction was stirred for 4 h. at room temp.
The reaction mixture was concentrated in vacuo and the crude residue was purified by chromatograph~~ (30o ethyl acetate/70o hexanes) to give 0.30 g (1000) of the title compound. This compound was sufficiently pure to be used in the next step.
Example 56 N-2- (4- (4- (2-azidoethyl) phenoxy) propyl.-2-propanesulfonamide.
O / \ / \ ~ 0 w N ~ \-.~ ~-H_S
O
N-2- ( 4- ( 4- ( 2- ( 0-methanesulfonyl ) e~thyi ) phenoxy) propyl-2-propanesulfonamide (0.30 g, 0.66 mmol, prepared in example 55) was combined with lithium azide (0.16 g, 3.3 mmol) in dry dimethylformamide (6 mL) and heated at reflux while stirring under N2 far 3 h. The reaction mixture was cooled to room temp. and concentrated in vacu.o. The crude residue WO flfl/06148 PCT/US99/16962 was purified by chromatography (1:1 (v/v) ethyl acetate/hexanes) to give 0.13 g (48%) of the title compound as a white crystalline solid.
LRMS (ES-) : 401 . 2 (M-2 ) Anal . Calc' d for C2oH26N4SO3 : C 59. 68, H 6. 72, N I3 .29; Found C 59.56, H 6.72, N 13.11.
Example 57 N-2-(4-(4-(2-aminoethyl)phenoxy)propy.l-2-propanesulfonamide hydrochloride.
O ~ ~ ~ ~ O
HCI H N N-S-<
H O
N-2-(4-(4-(2-azidoethyl)phenoxy)propyl-2-propanesulfonamide (0.10 g, 0.25 mmol, prepared in example 56) was combined with triphenylphosphine (0.079 g, 0.30 mmol) in THF (2 mL) and H20 (0.2 mL) and the reaction was heated at reflux overnight. The reaction mixture was cooled to room temp. and concentrated in vacuo. The crude residue was taken up in ethyl acetate and HCl gas was bubbled through the. solution until a white precipitate formed. The solid was collected by vacuum filtration and washed with ethyl acetate.
MS (ES+) : 377.4 (M+1) MS (ES-) : 375 . 3 (M-1 ) Anal. Calc' d for C2oH2BN203S~HCl (1/4 H2Cf) : C 56.92, H 7.16, N
6.64; Found C 56.78, H 7.06, N 6.54.

WO 00106148 PCT/US99/1.6962 Example 58 N-2-(4-(4-(2-(4-N-marpholino)ethyl)phenoxy)phenyl)propyl-2 propanesulfonamicLe.
\ -.
N S
HCI ~ H O
OJ
To a stirred solution of 4-(2-{4-morpholine)ethoxy)phenyl bromide (l.Og, 3.5 mmol) in 25 mL of '.CHF under Nz was added 1.8 mL (4.54 mmol) of a 2.5 M solution of n-BuLi at -78°C.
The mixture was stirred for 30 minutes and 0.48 mL (4.19 mmol) of trimethyl borate was added dropwise. Stirring was continued for 1.5 hours at -2 to 5°C then the reaction mixture was concentrated in vacuo. The resulting residual solid was dissolved in 20 mL of DME followed by addition of 1.0 g (3.12 mmol) of N-2-(4-bromophenyl)propyl-2-propanesulfonamide; 0.14 g (0.12 mmol) of tetrakis (triphenylphosphine) Pd ( 0) , 3 ..L2 mL ( 6.24 mmol) of 2 M
Na2C03 and 0 . 47 mL { 5 . 24 mmol ) of n-pr~~pyl alcohol, respectively. The resulting mixture was heated at reflux while stirring under N2 for 6 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with 30 mL of ethyl acetate and filtered through Celite.
Evaporation of the filtrate in vacuo i=ollowed by chromatography, eluting with 95:5 methylene chloride/methanol gave 0.22 g {17 0) of the desired compound as a yellow oil. The residue was dissolved in ether and a saturated solution of HCl in methanol was added dropwise until precipitation of a solid was obi>erved. The ether was decanted off and the resulting solid yaas triturated several times with ethyl acetate to afford thE: title compound as a white solid.

LRMS (ES-) : 445. 4 (M-1 ) Anal . Calc' d for C29H34N2OQS'HCl (H20) C 57 . 53, H 7 . 44, N
5.59; Found C 57.12, H 7.30, N 5.80.
Example 59 N-2-(4-((2-hydroxy)-ethoxy)-phenyl)-propyl-2-propanesulfonamide.
O ~ ~ O
HO~ H S \
O
To a stirred mixture lithium aluminum hydride (l mL, 1.0 mmol) in dry tetrahydrofuran (6 mL) wa.s added N-2-(4-((2-carboxylic acid)-ethoxy)-phenyl)-propyl-2-propanesulfonamide (0.250 g, .60 mmol) at OoC and under nitrogen. The resulting mixture was stirred for 3 h and allowed to warm to ambient temperature. To the mixture was then added water (30 uL), 15% solution of sodium hydroxide (30 uL), and lastly another portion of water (100 uL) which was stirred at ambient temperature for 1 h. The resulting mixture was filtered over celite and the solvents evaporated in vacuo.
The resulting product is added to a stirred mixture of dichloromethane: trifluoroacetic acid (2 mL, 1:1) under nitrogen. The resulting mixture was stirred at ambient temperature for 4 h. The mixture was partitioned between dichloromethane and 10~ aqueous potassium carbonate. The organic layer was washed with brine (1 X 20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate .in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 0.060 g (330) of the title compound.
Mass Spectrum: MS +1 = 302.2 Example 60 N-(2-((4-((benzamido)methyl)oxy)phenyl)propyl) 2 propanesulfonamide.
0 0 / \ O
/ \ N H ii~
H O
A solution of the acid from Preparation 17 (0.200 g, 0.48 mmol) in dry dimethylforamide (10 mL) was treated with aniline (0.05 mL, 0.58 mmol), Pip-Pip HOBT (0.222 g, 0.58 mmol, preparation 18) , and EDCI.HC1 (0.120 g, 0. 62 mmol) .
The resulting mixture was stirred at room temperature for 2 hour. The mixture was partitioned between dichloromethane and aqueous solution of HCl (10%). The organic layer was washed with water (2 x 10 mL) and brine (1 x 10 mL), dried over sodium sulfate, arid filtered. Evaporation of the filtrate in vacuo gave the protected product which was treated with a 1: 1 mixture of CH2C12: T~?A ( 6 mL) . The resulting mixture was stirred at room temperature for l2 hours. The mixture was partitioned between dichloromethane and aqueous solution of potassium carbonate. The organic layer was washed with water (2 x 10 mL~) and brine (1x14 mL), dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo to gave 0.152 g (81%) of the title compound.
Electrospray Mass Spectrum: 390.5 Analysis for C2oH26N204S

_77_ Example 61 N-(2-((4-((4-methylbenzamido)methyl}oxy)phenyl)propyl) 2 propanesulfonamid~e.
O 0 / \ ~ O
/ \ ~ ~-H-S
N O
H
The title compound was prepared from the product of Preparation 17 (0.100 g, 0.24 mmol) anal 4-methylaniline (0.03 mL, 0.29) in a manner analogous to the procedure described in Example 60.
Field Desorption Mass Spectrum: 404.5 Analysis for C2iH28N2O9S
Example 62 N- ( 2- ( ( 4- ( ( 4-isopropylbenzamido ) methyl ) oxy) phenyl ) propyl }
2-propanesulfonamide.
O p / \ O
/ \

H
The title compound was prepared from the product of Preparation 17 (0.100 g, 0.24 mmol) and 4-isopropylaniline (0.04 mL, 0.29mmo1) in a manner analogous to the procedure described in Example 60.
Field Desorption Mass Spectrum: 432.6 Analysis for C23H32N2O9S
Theory: C, 63.86; H, 7.45; N, 6.47.
Found C, 63.83; H, 7.59; N, 6.19.

Example 63 N-(2-((4-((4-methoxylbenzamido)methyl)oxy)phenyl)propyl) 2-propanesulfonamide.
p O / \ O
/ \ ~ H s O
The title compound was prepared from the product of Preparation 17 (0.100 g, 0.24 mmol) anal 4-isopropylaniline (0.036 g, 0.29 mmol) in a manner analogous to the procedure described in Example 60.
Field Desorption Mass Spectrum: 420.5 Analysis for C2sH2eN209S
Theory: C, 59.98; H, 6.71; N, 6.66.
Found C, 59.97; H, 6.78; N, 6:43.
Example 64 N- ( 2- ( ( 4- ( ( 3, 4-di f luorobenzamido ) acetyl ) oxy ) phenyl ) propyl ) 2-propanesulfonamide.
F O O / \ /
n I \ ~H S
F H O
The title compound was prepared from the product of Preparation 17 (0.150 g, 0.36 mmol) and 3,4-difluoroaniline (0.040 g, 0.43 mmol) in a manner analogous to the procedure described in Example 60.
Field Desorption Mass Spectrum: 426.5 ' ' WO 00/06148 PCT/US99/16.962 _79_ Example 65 Preparation of:
N / \ 0 / \~-N
Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, chloroacetyl chloride (0.971 g, 8.58mmo1) in 10 mL acetone was added dropwise to N-2-(4-aminophenyl)propyl 2-propanesulfonamide (2.00 g, 7:80 mmol, prepared in preparation 4) and Na2C03 ( 0.910 g, 8.,58 mmol} in 60 mL of acetone while stirring at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at this.
temperature for one hour. The solution was filtered over a celite~ mat and the resulting filtrate was concentrated under reduced vacuum to yield 3.00 g. of a white solid.
This material was purified via silica gel chromatography I5 employing the Water s prep. 2000 and eluting with a gradient solvent of methylene chloride to methylene chloride/ethyl acetate 9:1 over a 30 minute period to yield 2.16 g (84%) of the following chloro derivative:
N ~ \ 0 n H~~S~
CI O
as a slowly crystallizing oil mp 137.5°-138.5°C. The NMR
spectrum was consistent with the proposed structure. Ton spray M.S. 333.2 (M* + 1).
Tnto a flame dried 250 mL 3 necked flask fitted with stirrer, thermometer, and condenser, 3-hydroxypyridine (0.062 g, 0.54mmol ) in 10 mL DMF was added dropwise to NaH(0.030 g, 0.75 mmol) in 20 mL DMF while stirring at room temperature under a nitrogen atmosphere. After stirring far 45 minutes at this temperature, the above prepared chloro derivative (0.150 WO 00/06148 , PCTIUS99/16962 gØ45 mmol) in 20 mL DMF was added dropwise to the reaction followed by NaI(0.077 g, 0.51mmol) added spatula-wise. The reaction mixture was then heated at 100°C for 1.5 hours. The mixture was then cooled to room temperature and poured into 50 mL H20. The desired product was extracted with 50 mL ethyl acetate and the layers were separated,. The organic layer was washed once with H20, dried over K2C03, and concentrated under reduced vacuum to yield 0.181 g of an oil. This material was purified via silica gel chromatography employing the chromatotron using a 2000 micron rotor and eluting with a solvent ethyl acetate to yield 0.065 c~ (370) of the title compound as a yellow oil . The NMR spectrum was consistent with the proposed structure. Ion spray M.S. 392.2 (M* + 1) Example 66 Preparation of:
N / \ O
/ \ ~ ~ H S
~--0 0 0 ~N
Into a flame dried 250 mL 3 necked flask fitted with stirrer, thermometer, and condenser, 2.-hydroxypyridine (0.062 g, 0.540mmo1) in 10 mL DMF was added dropwise to NaH(0.030 g, 0.750 mmoi) in 20 mL DMF while stirring at room temperature under a nitrogen atmosphere. After starring for 45 minutes at this temperature, the chloro derivative prepared above in example 65 (0.150 g, 0.450 mmol) in 20 mL DMF was added dropwise to the reaction followed by. NaI (0.077 g, 0.510 mmol) added spatula-wise. The reaction mixture was then heated at 100°C for 1.5 hours. The mixture was then cooled to room temperature and poured into 50 mL H20. The desired product was extracted with 50 mL ethyl. acetate and the layers were separated. The organic layer wa~> washed once with H20,' dried over K2C03, and concentrated under reduced vacuum to yield 0.190 g of a foam. This material was purified via silica gel chromatography employing the chromatotron using a 2000 micron rotor and eluting with ethyl acetate to yield 0.040 g (23~) of the title compound as a white solid, mp 176°-178°C. The NMR spectrum was consistent with the proposed structure. Ion spray M.S. 392.2 (M* + 1) Analysis calculated for: C19H25N3OQS:
Theory: C, 58.29 H, 6:44 N, 10.73 Found: C, 57.89 H, 6.12 N, 10.55 Example 67 Preparation of:
N / \ o ~-N-S
\ H W

F
Into a flame dried 250 mL 3 necked flask fitted with stirrer, thermometer, and condenser, 4-chloro-3-fluorophenol (0.078 g, 0.54 mmol ) in 10 mL DMF was added dropwise to NaH( 0.030g, 0.75 mmol) in 20 mL DMF while .stirring at room temperature under a nitrogen atmosphere. After stirring for 45 minutes at this temperature, the ch.loro derivative prepared above in example 65 (0.150 g in 20 mL :DMF) was added dropwise to the reaction followed by NaT (0.077 g, 0.51 mmol) added spatula wise. The reaction mixture waa then heated at 100°C
for 1.5 hours. The mixture was then cooled to room temperature and poured into 50 mL H20. The desired product was extracted with 50 mL ethyl acetate and the layer, were separated. The organic layer was washed once with H20, dried over K2C03, and concentrated under reduced vacuum to yield 0:201 g. of an oil.
This material was purified via silica gel chromatography employing the chromatotron using a 2000 micron rotor and eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield 0.085 g (430) of the title compound as a yellow oil.
The NMR spectrum was consistent with the proposed structure.
Ion spray M.S. 443.2 (M* + 1) Example 68 Preparation of:
N ~ ~ O
-N-S--~
H ~y S O O
Into a flame dried 250 mL 3 necked flask fitted with stirrer, thermometer, and condenser, b~~nzenethiol (0.096 g, 0.87 mmol) in IO mL DMF was added dropwise to NaH (0.040 8, 1.00 mmol) in 20 mL DMF while stirring at room temperature under a nitrogen atmosphere. After stirring for 45 minutes at this temperature, the chloro derivative prepared in example 65 above (0.200 g, 0.60 mmol) in 20 mL DMF was added dropwise to the reaction followed by of NaT (0.102 g, 0.51 mmol) added spatula wise. The reaction mixture wars then heated at 100°C
for l.5 hours. The mixture was then cooled to room temperature and poured into 50 mL H20. The desired product was extracted with 50 mL ethyl acetate and the layers were separated. The organic layer was washed once with H20, dried over K2C03, and concentrated under reduced vacuum to yield 0.317 g. of an oil.
This material was purified via silica gel chromatography employing the chromatotron using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 1:1 to yield 0.100 g.(41o) of the title compound as a white solid The NMR
spectrrum was consistent with the proposed structure. Ion spray M.S. 407.4 (M* + 1).
Analysis calculated for: C2pH26N2~3S2-1/2 H20:
Theory: C, 57.79 H, 6.55 N, 6.74 i, _83_ Found: C, 57.84 H, 6.58 N, 6.66 Particularly preferred combinations of -(X2)-(L~m (Xsl.o)~ Xi (Lb)n ~ ~ O
_q H S \
O
are shown in Table I and can be prepared using known techniques and procedures, and techniques and procedures described herein, by one of ordinary skill in the art. The reagents and starting materials are readily available to one of ordinary skill in the art.
Table I.
N ~ ~ O
- N n H S \
O O
N ~ ~ O
ii ~H-S, O O
~N N I ~ 0 O _ --.~
O H
O O
O H
N ~ ~ O
-~-O v N _. S-~
H iW
O O
O
N ~ ~ O
H ~~-S--<
O O

O
4 O~N N / ~
' H H

___~__ H / \ (~
,~; N.~ N N - S
H

N N / \ O
W..;,N-S
O

a N / \ C1 ~ r y0 \_H-c~

N / \ O
,~:N~ n H S
O O
N / \ i) ~.( _;
H~ H ii~

0 / \ / ~ O
~i ~N~ H-g '__~ -- 0 O / \ / ~ O
~.N~ ~ ~H_S~
O
O / \ / ~ O
~--N-S
,O H y ' O

O / \ O
~H ~~
~) p / \ p n -;--N~ H~ S
O
O
N~ _.S
l_. O
I O / \ O
-O~ N-S--~
H ~E~~
O
O / \ CE
I
T.O ~H_S~~
O
O / \ Ci S~ H_s, ' O
o / \ p.
I
~N~ H_S
__~_. 0 O / \ O
O/~ .H S
O
T
' O
I
I

WO 00!06148 PCT/US99/16962 0 / \ 0 O H
O / \ o H_.S

, O O / \ O
ii T-N ~--~ H _ S _~
~H O
/ \ ~ \ O
p a O~ .H_S~
O
O / \ / \ O
o \r / t. ~'..~
O~ _H S \
,N
' ~ O
,H
0 / \ / \ p --'- N ~ Fi S
;i 0 H

Claims

We Claim:

1. A compound of the formula:

wherein:
La represents (1-4C)alkylene;
Lb represents (1-4C)alkylene;
Lc represents (1-4C)alkylene;
r is zero or 1;
m is zero or l;
n is zero or l;
q is 1 or 2;
X1 represents O, S, NR9, C(=O) , OCO, COO, NHCO2, O2CNH, CONH, NHCO, SO or SO2;
X2 represents O, S, NR11, C(=O) , OCO, COO, NHCO2, O2CNH, CONH, NHCO, SO or SO2;
X3 represents O, S, NR11, C(=O) , NHCO2, O2CNH, CONH, NHCO, SO
or SO2;
R1 represents a hydrogen atom, a (1-4C)alkyl group, a (3-8C)cycloalkyl group, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, or a saturated 4 to 7 membered heterocyclic ring containing the group NR10 and a group X as the only hetero ring members, wherein X represents -CH2-, CO, O, S or NR12 and R12 represents hydrogen or (1-4C);
R9 is hydrogen or (1-4C)alkyl;
R10 is hydrogen or (1-4C) alkyl, or R1 and R10 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, 4-di(1-4C)alkylaminopiperidinyl,-morpholino, piperazinyl or N-(1-4C)alkylpiperazinyl group;
R11 is hydrogen or (1-4C) alkyl;
R2 represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoro-alkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R3R4N in which R3 and R4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and either one of R5, R6, R7 and R8 represents hydrogen; (1-6C) alkyl; aryl (1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C) alkenyl or aryl, or two of R5, R6, R7 and R8 together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R5, R6, R7 and R8 represent hydrogen; or a pharmaceutically acceptable salt thereof, provided that (1) if m represents zero, then X1 represents C(=O), CONH, or SO2, X2 represents NR10 and R1 and R10 together with the nitrogen atom to which they are attached form an azetidinyl, piperidinyl, 4-di(1-4C)alkylaminopiperidinyl, piperazinyl or N-(1-4C)alkylpiperazinyl group, and (2) if the group --X2--(La)m --(X3Lc)r--X1--(Lb)n--represents -OCH2CONH-, then R1 does not represent an optionally substituted aromatic group or an optionally substituted heteroaromatic group.

2. A compound as claimed in Claim 1, wherein X1 represents O or CONH; X2 represents 0, NR10 wherein R10 represents hydrogen, methyl or, together with R1, pyrrolidinyl, piperidinyl, 4-(N,N-dimethylamino)piperidinyl or N-methylpiperazinyl, NHCO, CONH, OCO on OCONH; X3 represents O; L a represents methylene, ethylene, propylene or butylene;
L c represents methylene; m represents 1; and n represents zero.

3. A compound as claimed in Claim 1 or Claim 2, wherein R1 represents hydrogen, methyl, ethyl, propyl, t-butyl, cyclohexyl, phenyl, 4-isopropylphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2-fluorophenyl; 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2-trifluaromethylphenyl, 3-trifluaromethylphenyl, 4-trifluoromethylphenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl and, together with X2 when it represents NR10, pyrrolidinyl, piperidinyl, 4-(N,N-dimethylamino)-piperidinyl or N-methylpiperazinyl.

4. A compound as claimed in any one of Claims 1 to 3, wherein R2 represents (1-6C)alkyl, (1-6C)fluoroalkyl, (2-6C)alkenyl, or a group of formula R3R4N in which R3 and R4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group.

5. A compound as claimed in Claim 4, wherein R2 represents methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluoraphenyl, or dimethylamino.

6. A compound as claimed in Claim 5, wherein R2 represents ethyl, 2-propyl or dimethylamino.

7. A compound as claimed in any one of Claims 1 to 6 wherein R6 and R7 each represents hydrogen.

8. A compound as claimed in Claim 7, in which R8 represents methyl and R5 represents hydrogen.

9. A pharmaceutical composition, which comprises a compound as claimed in Claim 1 and a pharmaceutically acceptable diluent or carrier.

10. A method of potentiating glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a. compound as claimed in Claim 1 11. A method of treating a cognitive disorder; a neuro-degenerative disorder; age-related dementia; age-induced memory impairment; a movement disorder; reversal of drug-induced states; depression; attention deficit disorder;
attention deficit hyperactivity disorder; psychosis;
cognitive deficits associated with psychosis; or drug-induced psychosis in a patient, which comprises administering to a patient in need thereof an effective amount of a compound as claimed in Claim 1.

12. A method for improving memory or learning ability in a patient, which comprises administering to a patient in need thereof an effective amount of a compound as claimed in

Claim 1.